Saccharin derivatives useful as proteolytic enzyme inhibitors and compositions and method of use thereof

ABSTRACT

Novel 2-substituted saccharins which inhibit the enzymatic activity of proteolytic enzymes, are useful in the treatment of degenerative diseases and have the formula ##STR1## wherein: L is --O--, --S--, --SO--or --SO 2  --; 
     m and n are each independently 0 or 1; 
     R 1  is halo, lower-alkanoyl, 1-oxophenalenyl, phenyl or substituted phenyl, heterocyclyl or substituted heterocyclyl or, when L is --O-- and n is 1, cycloheptatrienon-2-yl or, when L is --S-- and n is 1, cyano or lower-alkoxythiocarbonyl or, when L is --SO 2  -- and n is 1, lower-alkyl or trifluoromethyl; R 2  is hydrogen, lower-alkoxycarbonyl, phenyl or phenylthio; and 
     R 3  and R 4  are each hydrogen or various substituents and processes for preparation and pharmaceutical compositions and method of use thereof are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 08/270,964 filedJul. 5, 1994, now abandoned, which is a division of application Ser. No.08/067,637 filed May 24, 1993, now U.S. Pat. No. 5,371,074, which is adivision of application Ser. No. 07/793,033 filed Nov. 15, 1991, nowU.S. Pat. No. 5,236,917, which is a continuation-in-part of applicationSer. No. 07/514,920 filed Apr. 26, 1990, now abandoned, which is acontinuation-in-part of application Ser. No. 07/347,125 file May 4,1989, now abandoned, and a continuation-in-part of application Ser. No.07/347,126 filed May 4, 1989 now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel 2-substituted saccharin derivatives,which inhibit the enzymatic activity of proteolytic enzymes, tocompositions containing the same, to the method of use thereof in thetreatment of degenerative diseases and to processes for theirpreparation.

2. Information Disclosure Statement

The inhibition of proteolytic enzymes by nontoxic reagents is useful inthe treatment of degenerative disorders, such as emphysema, rheumatoidarthritis and pancreatitis, in which proteolysis is a substantiveelement.

Protease inhibitors are widely utilized in biomedical research. Serineproteases are the most widely distributed class of proteolytic enzymes.Some serine proteases are characterized as chymotrypsin-like orelastase-like based upon their substrate specificity.

Chymotrypsin and chymotrypsin-like enzymes normally cleave peptide bondsin proteins at a site at which the amino acid residue on the carbonylside is typically Trp, Tyr, Phe, Met, Leu or another amino acid residuewhich contains aromatic or large alkyl side chains.

Elastase and elastase-like enzymes normally cleave peptide bonds at asite at which the amino acid residue on the carbonyl side of the bond istypically Ala, Val, Ser, Leu or other similar, smaller amino acids.

Both chymotrypsin-like and elastase-like enzymes are found inleukocytes, mast cells and pancreatic juice in higher organisms, and aresecreted by many types of bacteria, yeast and parasites.

Several classes of compounds are known to be serine protease inhibitors.For example Powers U.S. Pat. No. 4,659,855 discloses arylsulfonylfluoride derivatives useful as elastase inhibitors. Doherty et al. U.S.Pat. Nos. 4,547,371 and 4,623,645 disclose cephalosporin sulfones andsulfoxides, respectively, which are stated to be potent elastaseinhibitors useful in the treatment of inflammatory conditions,especially arthritis and emphysema.

Teshima et al., J. Biol. Chem., 257(9), 5085-5091 (1982) report theresults of studies on serine proteases (human leukocyte elastase,porcine pancreatic elastase, cathepsin G and bovine chymotrypsin Aa)with 4-nitrophenylesters and thioesters ofN-trifluoroacetylanthranilates, 2-substituted-4H-3,1-benzoxazin-4-ones,2-substituted-4-quinazolinones and 2-substituted-4-chloroquinazolines.

Cha, Biochem. Pharmacol., 24, 2177-2185 (1975) discusses kineticapproaches to the study of the binding of inhibitors to macromolecules,such as enzymes, and methods for determination of such parameters as theinhibition constants, reaction rates and bound and unbound enzymeconcentrations.

Certain 2-substituted saccharin derivatives are known to haveprotease-type enzyme inhibitory activity. For example Mulvey U.S. Pat.No. 4,195,023 discloses R₁ -2-R₂ CO-1,2-benzisothiazol-3-ones, where R₁is halogen, alkoxy, alkylamino, dialkylamino, alkoxycarbonyl, amino,nitro or hydrogen in the benzenoid ring thereof and R₂ is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, halophenyl, heteroaryl orsubstituted heteroaryl, and R₁ -2-A-CO-saccharins, where R₁ has the samemeanings as the benzenoid ring substituents in the1,2-benzisothiazol-3-ones and A is alkyl, alkenyl, alkynyl, cycloalkyl,fluorophenyl, heteroaryl or substituted-heteroaryl. The compounds aresaid to have elastase inhibitory activity and to be useful in thetreatment of emphysema.

Jones et al. , U.S. Pat. No. 4,276,298 discloses2-R-1,2-benzisothiazolinone-1,1-dioxides, where R is phenyl substitutedby fluoro, dinitro, trifluoromethyl, cyano, alkoxycarbonyl,alkylcarbonyl, carboxyl, carbamoyl, alkylacylamino, alkylsulfonyl,N,N-dialkylsulfamoyl, trifluoromethoxy, trifluoromethylthio,trifluoromethylsulfonyl and trifluoromethylsulfinyl, or pyridylsubstituted the same as R when R is phenyl except that pyridyl may alsobe mono-nitro substituted. The compounds are said to have proteaseenzyme inhibitory activity, especially elastase inhibitory activity, andto useful in the treatment of emphysema, rheumatoid arthritis "and otherinflammatory diseases".

Powers, Biochem., 24, 2048-2058 (1985) discloses studies of theinhibitions of four chymotrypsin-like enzymes, cathepsin G, rat mastcell proteases I and II, human skin chymase and chymotrypsin A.sub.α, byN-furoylsaccharin and N-(2,4-dicyanophenyl) saccharin.

Svoboda et al., Coll. Czech. Chem. Commun., 51, 1133-1139 (1986)disclose the preparation of4-hydroxy-2H-1,2-benzothiazine-3-carboxylates by intramolecularDieckmann condensation of2H-1,2-benzisothiazol-3-one-2-acetate-1,1-dioxide esters.

Chen, U.S. Pat. No. 4,263,393, Reczek et al. U.S. Pat. Nos. 4,350,752and 4,363,865 and Vanmeter et al. U.S. Pat. No. 4,410,618 relate tophotographic reagents (Reczek U.S. Pat. No. 4,350,752 and Vanmeter etal.), photographic dyes (Reczek U.S. Pat. No. 4,363,865) and"photographic elements and film units" (Chen) and disclose various2-substituted-saccharins useful for such applications, for example2-aroylmethylsaccharins by Chen, "photographic reagents" bound through aheteroatom to an "imidomethyl blocking" group (Reczek 4,350,752),"carrier-diffusible photographic dyes" bound to the nitrogen atom of animide through a 1,1-alkylene group (Reczek 4,363,865) andN-acylmethylimides which are described as "blocked photographicreagents" and which have a "residue of an organic photographic reagentcontaining a hetero atom through which it is bound to the blockinggroup" (Vanmeter). Reczek U.S. Pat. No. 4,350,752 specifically disclosesas "Compound 28" the species2-(1-phenyl-1H-tetrazol-5-ylthiomethyl)saccharin, and Vanmeterspecifically discloses a number of2-(1-R'-1H-tetrazol-5-ylthiomethyl)saccharins substituted on themethylene function by an aroyl or t-butylcarbonyl group.

Freed U.S. Pat. No. 3,314,960 discloses2-(1,1,3-trioxo-1,2-benzisothiazol-2-yl) glutarimides which are statedto be useful as sedatives.

Japanese Patent Publication 72/00419 discloses a number of2-RZ-methylsaccharins, stated to have strong activity against riceblast, rice sheath blight, rice helminthosporium leaf spot and ricebacterial leaf blight disease, wherein RZ is lower-alkoxy, butoxyethoxy,ethylthioethoxy, di-lower-alkylaminoethoxy, ethylthio, 2-chloroethoxy,1-(2-propenyloxy), 1-(2-propynyloxy), 2-saccharinylmethoxy, phenoxy (orphenoxy substituted by chlorine, methyl, nitro or methylthio),phenylthio, chlorophenylthio, benzylthio (or chlorobenzylthio), acetoxy,dichloroacetoxy, benzoyloxy (or benzoyloxy substituted by chlorine ornitro), acetylthio, dichloroacetyloxy, chlorobenzoylthio, methyl orethylcarbamyloxy, dimethylcarbamyloxy, phenylcarbamyloxy,ethylcarbamylthio, phenylcarbamylthio, dimethylthioylcarbamothioyl,ethylthiothioylthio, ethoxycarbonylthio, ethoxythioylthio andethylthiocarbonylthio.

2-Chloromethylsaccharin is disclosed in French Patent 1,451,417 as anintermediate for the preparation of N-methylsaccharind,1-trans-chrysanthemate, useful as an insecticide, and Lo U.S. Pat. No.3,002,884 discloses 2-chloro, 2-bromo and 2-iodomethylsaccharins, usefulas fungicidal agents.

SUMMARY

In a composition of matter aspect, this invention relates to2-substituted saccharin derivatives which have protease enzymeinhibitory activity and which are useful in the treatment ofdegenerative diseases.

In a composition aspect, the invention relates to compositions for thetreatment of degenerative diseases which comprise a pharmaceuticalcarrier and an effective proteolytic enzyme inhibiting amount of a2-substituted saccharin derivative.

In a method aspect, the invention relates to a method of use of the said2-substituted saccharins in the treatment of degenerative diseases whichcomprises administering to a patient in need of such treatment amedicament containing an effective proteolytic enzyme inhibiting amountof a said 2-substituted saccharin.

In a process aspect, the invention relates to a process for thepreparation of said 2-saccharin derivatives which comprises reacting a2-halomethylsaccharin either with an alkali metal salt of a L_(n) R₁moiety or with a L_(n) R₁ moiety in the presence of an acid-acceptor.

In further process aspects, the invention relates to a process for thepreparation of said 2-saccharin derivatives which comprises reacting analkali metal or thallous salt of a 2-unsubstituted saccharin either witha halo-CHR₂ --L_(n) R₁ moiety to obtain the desired product or with a3-chloro-3-(phenylthio) propyl-L_(n) R₁ species followed by oxidation ofthe product with a per acid to obtain a2-[1-(phenylsulfinyl)propyl-L_(n) R₁ ]saccharin and heating the latterto obtain a 2-[1-(2-propenyl)-L_(n) R₁ ]saccharin.

In a further process aspect, the invention relates to a process for thepreparation of 4-primary-lower-alkyl-R₄ -2-unsubstituted-saccharins,useful as intermediates for the preparation of the corresponding2-saccharin derivatives, which comprises reacting a 4-methyl-R₄-2-unsubstituted-saccharin with two molar equivalents of a lower-alkyllithium in an inert organic solvent and reacting the lithium salt thusproduced with one molar equivalent of a lower-alkyl halide.

In a further process aspect, the invention relates to a process for thepreparation of 4-primary- or secondary-lower-alkyl-R₄-2-unsubstituted-saccharins, useful as intermediates for the preparationof the corresponding 2-saccharin derivatives, which comprises reacting a2-primary-lower-alkyl-N,N-di-lower-alkylbenzamide with a lower-alkyllithium in an inert organic solvent; reacting the resulting lithium saltwith a lower-alkyl halide; reacting the resulting 2-primary orsecondary-lower-alkyl-R₄ -N,N-di-lower-alkylbenzamide with a lower-alkyllithium; reacting the resulting lithium salt with sulfur dioxidefollowed by hydroxylamine-sulfonic acid in the presence of base; andheating the product in an acid medium.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

More specifically this invention relates to 2-substituted saccharinderivatives having the formula: ##STR2## wherein: L i s --O--, --S--,--SO-- or --SO₂ --;

m and n are each independently 0 or 1;

R₁ is halogen, lower-alkanoyl, 1-oxo-phenalenyl, phenyl (or phenylsubstituted by halogen, lower-alkyl, lower-alkoxy, nitro, amino,lower-alkylamino or di-lower-alkylamino) or heterocyclyl selected from1H-(5-tetrazolyl), 5-oxo-1-tetrazolyl, 5-thioxo-1-tetrazolyl (when R₂ asdefined hereinbelow is other than phenylthio), pyrimidinyl,2-benzoxazolyl, 2-benzothiazolyl, 2-phthalimidyl,2-(1,3,4-thiadiazolyl), 5-(1,2,4-thiadiazolyl),5-thioxo-3-(1,2,4-thiadiazolyl), 4-(5-oxo-1,3,4-thiadiazolyl),4-(5-thioxo-1,3,4-thiadiazolyl), 3-(1,2,4-triazolyl),4-(1,2,4-triazolyl), (1,2,3-triazolyl), 2-imidazolyl or3-(1,2,4-triazolo[4,3-a]pyridinyl), or such heterocyclyl groupssubstituted on any available nitrogen atom by lower-alkyl,hydroxy-lower-alkyl, cycloalkyl, 2-, 3- or 4-pyridinyl,carboxy-lower-alkyl, lower-alkoxycarbonyl-lower-alkyl,aminocarbonyl-lower-alkyl, lower-alkylaminocarbonyl-lower-alkyl,di-lower-alkylaminocarbonyl-lower-alkyl, amino-lower-alkyl,lower-alkylaminolower-alkyl, di-lower-alkylamino-lower-alkyl,4-morpholinyl-lower-alkyl, 1-piperidinyl-lower-alkyl,1-pyrrolidinyl-lower-alkyl or phenyl (or phenyl substituted by amino,lower-alkylamino, di-lower-alkylamino, lower-alkanamido,N-lower-alkyl-lower-alkanamido, carboxy-lower-alkanamido, carboxy,lower-alkoxycarbonyl, lower-alkoxy or halogen), or such heterocyclylgroups substituted on any available carbon atom by nitro, lower-alkyl,amino, lower-alkylamino, di-lower-alkylamino, cycloalkylamino, mercapto,lower-alkylthio, amino-lower-alkylthio,lower-alkylamino-lower-alkylthio, di-lower-alkylamino-lower-alkylthio,4-morpholinyl-lower-alkylthio, 1-piperidinyl-lower-alkylthio,1-pyrrolidinyl-lower-alkylthio, lower-alkoxycarbonyl or phenyl (orphenyl substituted by amino, lower-alkylamino, di-lower-alkylamino,lower-alkanamido, N-lower-alkyl-lower-alkanamido, lower-alkyl,lower-alkoxy or halogen);

R₂ is hydrogen, lower-alkoxycarbonyl, phenyl or phenylthio;

R₃ is hydrogen, halogen, primary or secondary lower-alkyl, lower-alkoxy,lower-alkoxycarbonyl, phenyl, fluoro-lower-alkyl, lower-alkenyl orcyano;

R₄ is hydrogen or from one to two substituents selected from halogen,cyano, nitro, amino, lower-alkanamido, phenyl-lower-alkanamido,diphenyl-lower-alkanamido, lower-alkylsulfonylamino, polyfluoro-lower-alkylsulfonylamino, aminosulfonyl, lower-alkyl, polyhalo-lower-alkyl,cycloalkyl, polyhalo-lower-alkoxy, hydroxy, lower-alkoxy, carboxy,hydroxymethyl, formyl, aminomethyl, lower-alkylsulfonyl,polyhalo-lower-alkylsulfonyl, lower-alkylsulfonylaminosulfonyl andlower-alkoxypoly-lower-alkyleneoxy; and wherein the --CHR₂ -- group isalways appended either to a hetero atom of the L moiety as defined aboveor it is appended to a hetero atom of the R₁ moiety, with the provisosthat (i) when m and n are 0 and R₂, R₃ and R₄ are all hydrogen, R₁cannot be halogen; (ii) when m is 0, n is 1, L is --S-- and R₂, R₃ andR₄ are each hydrogen, R₁ cannot be 1-phenyl-1H-(5-tetrazolyl); (iii)when m is 0, n is 1, L is --O--or --S--, and R₂, R₃ and R₄ are allhydrogen, R₁ cannot be lower-alkanoyl; (iv) when m is 0, n is 1, L is--O--, --S-- or --SO--, and R₂, R₃ and R₄ are all hydrogen, or when m is0, n is 1, L is --S--, R₂ and R₄ are hydrogen and R₃ is halogen, or whenm is 0, n is 1, L is --SO-- or --SO₂ --, R₂ is lower-alkoxycarbonyl andR₃ and R₄ are both hydrogen, R₁ cannot be phenyl or substituted phenyl.

Preferred compounds of Formula I above are those wherein:

L i s --O--, --S--, --SO-- or --SO₂ --;

m and n are each independently 0 or 1;

R₁ is halogen, lower-alkanoyl, 1-oxo-6- or 7-phenalenyl, phenyl (orphenyl substituted by halogen or nitro) or heterocyclyl selected from1H-(5-tetrazolyl), 5-oxo-1-tetrazolyl, 5-thioxo-1-tetrazolyl (when R₂ asdefined hereinbelow is other than phenylthio), pyrimidinyl,2-benzoxazolyl, 2-benzothiazolyl, 2-phthalimidyl,2-(1,3,4-thiadiazolyl), 5-(1,2,4-thiadiazolyl),4-(5-oxo-1,3,4-thiadiazolyl), 4-(5-thioxo-1,3,4-thiadiazolyl),3-(1,2,4-triazolyl), 4-(1,2,3-triazolyl), 2-imidazolyl or3-(1,2,4-triazolo[4,3-a]pyridinyl), or such heterocyclyl groupssubstituted on any available nitrogen atom by lower-alkyl,hydroxy-lower-alkyl, cycloalkyl, 3- or 4-pyridinyl, carboxy-lower-alkyl,lower-alkoxycarbonyl-lower-alkyl,di-lower-alkylaminocarbonyl-lower-alkyl, 4-morpholinyl-lower-alkyl orphenyl (or phenyl substituted by amino, lower-alkanamido,carboxy-lower-alkanamido, carboxy or lower-alkoxycarbonyl, or suchheterocyclyl groups substituted on any available carbon atom by nitro,lower-alkyl, amino, cycloalkylamino, mercapto, lower-alkylthio,di-lower-alkylamino-lower-alkylthio, 4-morpholinyl-lower-alkylthio,1-piperidinyl-lower-alkylthio, lower-alkoxycarbonyl or phenyl (or phenylsubstituted by lower-alkanamido);

R₂ is hydrogen, carbo-lower-alkoxy, phenyl or phenylthio;

R₃ is hydrogen, halogen, primary or secondary-lower-alkyl, lower-alkoxy,lower-alkoxycarbonyl, phenyl, fluoro-lower-alkyl, lower-alkenyl orcyano; and

R₄ is hydrogen, halogen, nitro, diphenyl-lower-alkanamido, lower-alkyl,hydroxy, lower -alkoxy or lower-alkoxyethoxyethoxy.

Other preferred compounds are those of formula I above wherein:

L is --S--, --SO-- or --SO₂ --;

m and n are each independently 0 or 1;

R₁ is 1-oxo-6- or 7-phenalenyl or heterocyclyl selected from1H-(5-tetrazolyl), 5-oxo-1-tetrazolyl, 5-thioxo-1-tetrazolyl (when R₂ asdefined hereinbelow is other than phenylthio), pyrimidinyl,2-benzoxazolyl, 2-benzothiazolyl, 2-phthalimidyl,2-(1,3,4-thiadiazolyl), 5-(1,2,4-thiadiazolyl),4-(5-oxo-1,3,4-thiadiazolyl), 4-(5-thioxo-1,3,4-thiadiazolyl),3-(1,2,4-triazolyl), 4-(1,2,3-triazolyl), 2-imidazolyl or3-(1,2,4-triazolo[4,3-a]pyridinyl) or such heterocyclyl groupssubstituted on any available nitrogen atom by lower-alkyl,hydroxy-lower-alkyl, cycloalkyl, 3- or 4-pyridinyl, carboxy-lower-alkyl,lower-alkoxycarbonyl-lower-alkyl,di-lower-alkylaminocarbonyl-lower-alkyl, 4-morpholinyl-lower-alkyl orphenyl (or phenyl substituted by amino, lower-alkanamido,carboxy-lower-alkanamido, carboxy or lower-alkoxycarbonyl), or suchheterocyclyl groups substituted on any available carbon atom by nitro,lower-alkyl, amino, cycloalkylamino, mercapto, lower-alkylthio,di-lower-alkylamino-lower-alkylthio, 4-morpholinyl-lower-alkylthio,1-piperidinyl-lower-alkylthio, lower-alkoxycarbonyl or phenyl (or phenylsubstituted by lower-alkanamido);

R₂ is hydrogen, lower-alkoxycarbonyl, phenyl or phenylthio;

R₃ is hydrogen, halogen, primary or secondary-lower-alkyl, lower-alkoxy,lower-alkoxycarbonyl or phenyl; and

R₄ is hydrogen, halogen, nitro, diphenyl-lower-alkanamido, lower-alkyl,hydroxy, lower-alkoxy or lower-alkoxyethoxyethoxy.

Particularly preferred compounds are those of formula I wherein: m is 0or 1; n is 1; L is --S--; R₂ is hydrogen; R₃ is halogen, primary orsecondary-lower-alkyl, lower-alkoxy, lower-alkoxycarbonyl or phenyl; andR₁ is 1H-(5-tetrazolyl), 5-oxo-1-tetrazolyl, 5-thioxo-1-tetrazolyl or2-(1,3,4,-thiadiazolyl) or such groups substituted on a ring carbon ornitrogen atom thereof by substituents as defined above.

It should be understood that the compounds having the general structuralformula I are usually named in the chemical literature as1,2-benzisothiazol-(2H)-3-one-1,1-dioxides. However for the sake ofbrevity, such compounds are frequently named as saccharin derivatives,and that nomenclature will be used hereinafter in describing thecompounds of the invention and their biological properties.

As used herein the terms lower-alkyl, lower-alkoxy and lower-alkane meanmonovalent aliphatic radicals, including branched chain radicals, offrom one to ten carbon atoms. Thus the lower-alkyl (or lower-alkane)moiety of such groups include, for example, methyl, ethyl, propyl,isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 2-methyl-3-butyl,1-methylbutyl, 2-methylbutyl, neopentyl, n-hexyl, 1-methylpentyl,3-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 2-hexyl, 3-hexyl,1,1,3,3-tetramethylpentyl, 1,1-dimethyloctyl and the like.Lower-alkanoyl has from two to ten carbon atoms and is branched orunbranched.

As used herein the term halogen (or halo) means fluorine, chlorine,bromine or iodine.

As used herein the term cycloalkyl means carbocyclic rings having fromthree to six ring carbon atoms, including cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl which may be substituted on any ring carbonatom thereof by one or more lower-alkyl groups.

As used herein the term lower-alkenyl means monovalent, unsaturatedradicals, including branched chain radicals, of from three to ten carbonatoms and thus includes 1-(2-propenyl), 1-(2-butenyl),1-(1-methyl-2-propenyl), 1-(4-methyl-2-pentenyl),4,4,6-trimethyl-2-heptenyl and the like.

The compounds of the present invention inhibit the activity of serineproteases, specifically human leukocyte elastase and thechymotrypsin-like enzymes, and are thus useful in the treatment ofdegenerative disease conditions such as emphysema, rheumatoid arthritisand pancreatitis. In the process of binding to, and inhibiting, theactivity of a proteolytic enzyme, it is believed that the compounds ofthe invention are cleaved at the bond between the methylene (CHR₂) andthe L_(n) R₁ functions, and that the L_(n) R₁ group is split off as ananion which can thus be described as a "leaving group". This cleavage isbelieved to be facilitated by the presence of an "electron withdrawinggroup", such as cyano, halogen, nitro, carboxy, lower-alkoxycarbonyl,acyl or phenylthio, in the R₁ functionality to thereby increase itselectro-negativity, which can be expressed in terms of the pKa values ofthe acid form of the "leaving group" which ideally should be less thanabout 7. A particularly preferred group of such compounds are those offormula I where R₃ is other than hydrogen.

The compounds of formula I where m is 0, R₂ is hydrogen and L is --I--or --S-- are prepared by reaction of a 2-halomethylsaccharin derivativeof formula I where R₁ is halogen, R₂ is hydrogen, m and n are 0 and R₃and R₄ have the meanings given above, with an appropriate L_(n) R₁moiety. The reaction can either be carried out in the presence of anacid-acceptor, such as an alkali metal carbonate, atri-lower-alkylamine, an alkali metal or thallous-lower-alkoxide or analkali metal hydride, or alternatively an alkali metal salt of the L_(n)R₁ moiety can be used. The reaction is carried out in an organic solventinert under the conditions of the reaction, for example acetone, methylethyl ketone (MEK), tetrahydrofuran (THF), diethyl ether,dimethylformamide (DMF), methylene dichloride (MDC) or lower-alkanols,at a temperature in the range from ambient up to the boiling point ofthe solvent used. The corresponding compounds where L is --SO-- or --SO₂-- are prepared by oxidation of the corresponding compounds of formula Iwhere L is --S-- with one or two molar equivalents, as appropriate, of aperacid, such as 3-chloroperbenzoic acid.

Alternatively, the compounds of formula I where m is 0 can be preparedby reaction of an alkali metal or thallous saccharin salt (prepared byreaction of an appropriate 4-R₃ -R₄ -2-unsubstituted saccharin with analkali metal alkoxide or a thallous lower-alkoxide) with a halo-CHR₂-L_(n) R₁ moiety, where R₁, R₂, R₃, R₄, L and n have the meanings givenabove with respect to formula I. A thallium salt can be used when R₂ hasall the meanings given above, but an alkali metal salt can be used onlywhen R₂ is hydrogen. The reaction is carried out in an inert organicsolvent, for example a lower-alkanol or DMF, at temperatures in therange from 20° C. to the boiling point of the solvent used.

The compounds of formula I where m is 1 and R₂ is hydrogen are preparedby reaction of a 3-(phenylthio) propyl-L_(n) R₁ compound, prepared byreaction of a L_(n) R₁ -propyl halide with sodium thiophenoxide inmethyl ethyl ketone (MEK), followed by reaction of the product withN-chlorosuccinimide to give a 3-chloro-3-(phenylthio)propyl-L_(n) R₁species. Reaction of the latter with a thallium salt of an appropriate4-R₃ -R₄ -saccharin, using the same conditions described above for thepreparation of the compounds of formula I from a saccharin salt and ahalo-CHR₂ -L_(n) R₁ moiety, affords a 2-[1-(phenylthio) propyl-L_(n) R₁]saccharin. Oxidation of the latter to the corresponding2-[1-(phenylsulfinyl)propyl-L_(n) R₁ ]saccharin followed by heating theproduct in an alkylene glycol ether, for example ethylene glycoldimethyl ether, affords the compounds of formula I where m is 1 and R₂is hydrogen.

The compounds of formula I, where R₁ is lower-alkanoyl, R₂ is hydrogen,L is --O--, m is 0, n is 1, and R₃ and R₄ have the meanings given above,are prepared by treating the corresponding 2-hydroxymethylsaccharin withan appropriate acid anhydride in the presence of a catalytic amount of amineral acid or a strong organic acid, for example sulfuric acid orp-toluenesulfonic acid.

The 2-halomethylsaccharins of formula I where R₁ is halogen, R₂ ishydrogen, m and n are 0, and R₃ and R₄ have the meanings given abovewith respect to formula I, and the corresponding 4-R₃ -R₄-2-unsubstituted saccharins required for the preparation of thecompounds of formula I where R₁, L, m and n have the other meaningsgiven above, are prepared by the methods described by D'Alelio et al.,J. Macromol. Sci-Chem., A3 (5), 941 (1969) and Saari et al. , J. Het.Chem. , 23, 1253 (1986). In the method described by Saari, a methylester of an appropriate anthranilic acid is prepared by conventionalmeans from the substituted anthranilic acid and the ester diazotized.The diazonium salt is then reacted with sulfur dioxide and cupricchloride to produce a sulfonyl chloride which is then reacted withconcentrated ammonium hydroxide to produce the substituted saccharinderivatives of formula II. The latter, on reaction with formaldehyde ina lower-alkanol solvent affords the 2-hydroxymethylsaccharins of formulaIII, which, on reaction with a thionyl halide or a phosphorus trihalide,afford the corresponding 2-halomethylsaccharin derivatives. The approachis illustrated as follows: ##STR3## where R₃ and R₄ have the meaningsgiven above and X is halogen.

The halomethylsaccharins of formula I, where R₁ is halogen, R₂ ishydrogen, m and n are 0, and R₃ and R₄ have the meanings given abovewith respect to formula I, can also be prepared by reaction of acorresponding 2-phenylthiomethylsaccharin with a sulfuryl halide in aninert organic solvent, for example MDC, ethylene dichloride (EDC) orcarbon tetrachloride, at a temperature from around 0° C. to around 30°C.

The compounds of formula II where R₃ is either primary or secondarylower-alkyl, and which are useful as intermediates for the preparationof the compounds of formula I as described above, are prepared by one oftwo methods. The compounds of formula II where R₃ is primary lower-alkylare prepared by reacting a 4-methyl-R₄ -2-unsubstituted-saccharin withtwo molar equivalents of a lower-alkyl lithium in an inert organicsolvent, for example THF, and reacting the resulting lithium salt withone molar equivalent of a lower-alkyl halide, both reactions beingcarried out at a temperature in the range from about -50° C. to -80° C.

The compounds of formula II where R₃ is either primary or secondarylower-alkyl are prepared by reaction of a 2-primary-lower-alkyl-R₄-N,N-di-lower-alkylbenzamide with one molar equivalent of a lower-alkyllithium in the presence of a tetra-lower-alkylethylenediamine in aninert organic solvent, for example THF and reaction of the resultinglithium salt with one molar equivalent of a lower-alkyl halide at atemperature in the range from about -50° C. to -80° C. The resulting2-primary- or secondary-lower-alkyl-R₄ -N,N-di-lower-alkylbenzamide isthen reacted with one molar equivalent of a lower-alkyl lithium in thepresence of a tetra-lower-alkylethylenediamine in an inert organicsolvent, for example THF, and the resulting lithium salt reacted withsulfur dioxide at a temperature in the range from -50° C. to -80° C.followed by reaction of the product with hydroxylaminesulfonic acid inthe presence of base. The resulting 2-lower-alkyl-R₄-6-aminosulfonyl-N,N-di-lower-alkylbenzamide is thereafter heated in anacid medium to effect cyclization of the latter to the desired 4-primaryor secondary lower-alkyl-R₄ -2-unsubstituted-saccharin of formula II. Itis preferred to carry out the cyclization in refluxing glacial aceticacid. When the 2-lower-alkyl group in the 2-lower-alkyl-R₄-N,N-di-lower-alkylbenzamide starting material is methyl, alkylationaffords species where the 2-lower-alkyl group is either straight orbranched depending upon whether a straight or branched chain lower-alkylhalide is used for the alkylation. On the other hand, when the2-lower-alkyl group in the starting material contains more than onecarbon atom, alkylation takes place on the carbon atom adjacent thebenzene ring and affords products having a sec.-lower-alkyl group at the2-position.

Access to certain of the required intermediates of formula II in somecases requires building up the two rings making up the saccharinnucleus. Thus to prepare compounds where R₃ is lower-alkoxy and R₄ is7-hydroxy, 3,3-dithiobispropionic acid is converted to the his acidchloride by reaction of the acid with thionyl chloride, and the acidchloride is then reacted with two molar equivalents of benzylamine toproduce the bis n-benzylamide. The latter, on reaction with sulfurylchloride in an organic solvent, such as MDC, EDC or carbontetrachloride, affords 5-chloro-2-benzyl-2H-isothiazol-3-one, which isoxidized with one molar equivalent of a per acid, such as perbenzoicacid or 3-chloroperbenzoic acid, to5-chloro-2-benzyl-2H-isothiazol-3-one-1-oxide. The latter, on heatingunder pressure with a 2-lower-alkoxyfuran in an organic solvent, such asbenzene, toluene or xylene, affords a4-lower-alkoxy-7-hydroxy-2-benzyl-1,2-benzisothiazol-2H-3-one-1-oxide.The 7-hydroxy group can, if desired, then be reacted with a lower-alkylhalide or a lower-alkoxypoly-lower-alkoxy-lower-alkyl halide to give thecorresponding 4,7-di-lower-alkoxy or4-lower-alkoxy-7-lower-alkoxypoly-lower-alkyleneoxy-2-benzyl-1,2-benzisothiazol-2H-3-one-1-oxide.Further oxidation of the product with one molar equivalent of a per acidas described before followed by catalytic debenzylation affords thecorresponding 4-lower-alkoxy-7-R₄ -2-unsubstituted saccharins.

Other simple chemical transformations which are conventional and wellknown to those skilled in the art of chemistry can be used for effectingchanges in functional groups in the compounds of the invention. Forexample, catalytic reduction of nitro groups to produce thecorresponding amino substituted compounds, acylation ofamino-substituted species to prepare the corresponding amides oroxidation of sulfides or sulfoxides to prepare the corresponding,respective sulfoxides or sulfones as desired can be carried out.

In standard biological test procedures, the compounds of formula I havebeen found to possess human leukocyte elastase (HLE) and chymotrypsininhibitory activities, and are thus useful in the treatment ofdegenerative diseases, such as emphysema, rheumatoid arthritis orpancreatitis.

The compounds of formula I having basic functions can be converted tothe acid-addition salt form by interaction of the base with an acid. Inlike manner, the free base can be regenerated from the acid-additionsalt form in conventional manner, that is by treating the salts withcold, weak aqueous bases, for example alkali metal carbonates and alkalimetal bicarbonates. The bases thus regenerated can be interacted withthe same or a different acid to give back the same or a differentacid-addition salt. Thus the bases and all of their acid-addition saltsare readily interconvertible.

Likewise certain compounds of formula I having acid, i.e. carboxylicacid, functions can be converted to salt forms thereof by reaction ofthe acid with a base, such as alkali metal or ammonium hydroxides orwith organic bases such as alkyl, dialkyl or trialkylamines, and theacids can be regenerated from the salts by treatment of the salts withaqueous acids.

It will thus be appreciated that formula I not only represents thestructural configuration of the bases and acids of formula I but is alsorepresentative of the structural entities which are common to all of thecompounds of formula I whether in the form of the free base, the freeacids or in the form of the salts of the bases and acids. It has beenfound that, by virtue of these common structural entities the compoundsof formula I and their salts have inherent pharmacological activity of atype to be more fully described hereinbelow. This inherentpharmacological activity can be enjoyed in useful form forpharmaceutical purposes by employing the free bases or free acidsthemselves or the salts formed from pharmaceutically acceptable acidsand bases, that is acids or bases whose anions or cations are innocuousto the animal organism in effective doses of the salts so thatbeneficial properties inherent in the common structural entityrepresented by the free bases and free acids are not vitiated by sideeffects ascribable to the anions or cations.

In utilizing this pharmacological activity of the salts, it ispreferred, of course, to use pharmaceutically acceptable salts. Althoughwater insolubility, high toxicity or lack of crystalline character maymake some particular salt species unsuitable or less desirable for useas such in a given pharmaceutical application, the water-insoluble ortoxic salts can be converted to the corresponding pharmaceuticallyacceptable bases by decomposition of the salts with aqueous base oraqueous acid as explained above, or alternatively they can be convertedto any desired pharmaceutically acceptable salt by double decompositionreactions involving the anion or cation, for example by ion-exchangeprocedures.

Moreover, apart from their usefulness in pharmaceutical applications,the salts are useful as characterizing or identifying derivatives of thefree bases or free acids or in isolation or purification procedures.Like all of the salts, such characterizing or purification saltderivatives can, if desired, be used to regenerate the pharmaceuticallyacceptable free bases or free acids by reaction of the salts withaqueous base or aqueous acid, or alternatively they can be converted toa pharmaceutically acceptable salt by, for example, ion-exchangeprocedures.

The novel feature of the compounds then resides in the concept of thebases and the cationic and anionic forms of the 4-R₃ -R₄ -2-substitutedsaccharins of formula I and not in any particular acid or base moiety oracid anion or base cation associated with the salt forms of thecompounds; rather, the acid or base moieties or the anions or cationswhich can be associated with the salt forms are in themselves neithernovel nor critical and therefore can be any acid anion or base cationcapable of salt formation with the bases or acids.

The compounds of formula I of the invention can be prepared forpharmaceutical use by incorporating them in unit dosage form as tabletsor capsules for oral administration either alone or in combination withsuitable adjuvants such as calcium carbonate, starch, lactose, talc,magnesium stearate, gum acacia and the like. Still further, thecompounds can be formulated for oral, parenteral or aerosol inhalationadministration either in aqueous solutions of water soluble salts of thecompounds or in aqueous alcohol, glycol or oil solutions or oil-wateremulsions in the same manner as conventional medicinal substances areprepared.

The percentages of active component in such compositions may be variedso that a suitable dosage is obtained. The dosage administered to aparticular patient is variable, depending upon the clinician's judgmentusing as criteria: the route of administration, the duration oftreatment, the size and physical condition of the patient, the potencyof the active component and the patient's response thereto. An effectivedosage amount of the active component can thus only be determined by theclinician after a consideration of all criteria and using his bestjudgment on the patient's behalf.

The molecular structures of the compounds of the invention were assignedon the basis of study of their infrared and NMR spectra. The structureswere confirmed by the correspondence between calculated and found valuesfor elementary analyses for the elements.

The following examples will further illustrate the invention without,however, limiting it thereto. All melting points are uncorrected.

EXAMPLE 1

Powdered potassium hydroxide (7.4 g; 132 mmol; 2 equiv.) was admixedwith dimethyl sulfoxide (DMSO) (100 ml ), and the mixture was stirredfor 5 minutes. 6-Methylanthranilic acid (10.0 g; 66 mmol) was then addedto the mixture and iodomethane (4.52 ml; 73 mmol; 1.1 equiv.) addeddropwise. The reaction mixture was stirred for 30 minutes at roomtemperature, then diluted with ether (250 ml), washed with water (3×100ml), dried (MgSO₄) and concentrated. The crude product was filteredthrough a pad of flash grade (32-63) silica gel and eluted with 1:9ether:hexane to afford 4.23 g (39%) of methyl 6-metbylanthranilate as anoil. ¹ H nmr (300 MHz, CDCl₃): 7.078 (1H, t, J=7.67 Hz); 6.529 (2H, d,J=7.79 Hz); 5.111 (2H, br s) ; 3.887 (3H, s); 2.424 (3H, s). IR (neatfilm, cm¹): 3480 (m), 3380 (m), 2950 (w), 1690 (s); 1605 (s).

The methyl 6-methylanthranilate prepared in (a) (4.23 g; 25.6 mmol) wasdissolved in acetic acid (25 ml) and the solution cooled to 0° C.Concentrated hydrochloric acid (45 ml) was added to produce a tanslurry. A solution of sodium nitrite (1.89 g; 27.4 mmol; 1.07 equiv.) inwater (8 ml) was added dropwise with stirring, the resulting orangesolution was stirred at 0° C. for 1 hour and then added in 6 portions toa mixture of cupric chloride dihydrate (2.18 g; 12.8 mmol; 0.5 equiv.)and sulfur dioxide (6.3 g; excess) in acetic acid (33 ml) and water (6ml) at 0° C. The dark green solution was stirred at room temperatureovernight, poured into ice-water (300 ml), and the solid which separatedwas collected and dried by suction to provide 1.11 g of the sulfonylchloride which was immediately added to ice cold ammonium hydroxide (100ml) and stirred at room temperature overnight. The solution wasacidified to pH 1 with concentrated HCl and the resulting precipitatewas collected and air-dried to provide 729 mg (12%) of4-methylsaccharin, mp 224°-226° C. ¹ H nmr (300 MHz, CD₃ CN): 9.5 (1H,br s); 7.782 (2H, d, J=4.35 Hz); 7.644 (1H, t, J-4.20 Hz); 2.683 (3H,s). IR (KBr, cm¹): 3400 (w); 3100 (s); 3000 (s); 1720 (s); 1580 (m).FDMS: m/e 197 (M⁺).

4-Methylsaccharin prepared in (b) (500 mg; 2.54 mmol) was dissolved in2.53 ml of warm ethanol (steam bath). Once a homogeneous solution wasachieved, formalin (37% in methanol; 1.76 ml excess) was added dropwise.The solution was allowed to cool to room temperature and then chilled to0° C. for 4 days. The resulting solid was collected and air-dried toafford 476 mg (82%) of 2-hydroxmethyl-4-methylsaccharin, mp 196°-198° C.¹ H nmr (300 MHz, CDCl₃): 7.767 (1H, t, J=6.75 Hz); 7.732 (1H, d, J=7.72Hz); 7.600 (1H, d, J=6.64 Hz); 5.361 (2H, d, J-8.00 Hz); 3.296 (1H, t,J=8.16 Hz); 2.793 (3H, s). IR (KBr, cm¹): 3505 (s); 3070 (w); 1735 (s);5180 (m).

2-Hydroxymethyl-4-methylsaccharin produced in (c) (76 mg; 0.33 ml) wasadmixed with acetic anhydride (1 ml; excess), and 2 drops ofconcentrated sulfuric acid were added. The reaction mixture was stirredfor 2 hours at room temperature, at which time a non-polar spot wasobserved by thin-layer chromatographic (tlc) analysis. The reactionmixture was diluted with MDC (50 ml) and washed with saturated sodiumbicarbonate (2×15 ml). After drying (Na₂ SO₄), the solvent was removedto afford 64 mg (72%) of 2-acetoxymethyl-4-methylsaccharin, mp 198°-205°C. (decomp.) ¹ H nmr (300 MHz, CDCl₃): 7.8 (2H, m); 7.64 (1H, d, J=6.18Hz); 5.84 (2H, s); 2.82 (3H, s); 2.15 (3H, s). IR (KBr, cm¹): 2920 (w);1745 (s); 1735 (s); 1630 (w). FDMS: m/e 269 (M⁺).

EXAMPLE 2

Using the procedure described above in Example 1, 6-chloroanthranilicacid (5.00 g; 29.2 mmol) and iodomethane (2.75 ml; 44 mmol; 1.5 equiv.)were reacted in the presence of powdered potassium hydroxide (4.08 g;72.7 mmol; 2.5 equiv.) to give 4.22 g (78%) of methyl6-chloroanthranilate as an oil. ¹ H nmr (300 MHz, CDCl₃): 7.077 (1H, t,J=8.06 Hz); 6.744 (1H, d, J=6.7 Hz); 6.575 (1H, d, J=8.25 Hz); 4.871(1H, br s); 3.929 (3H, s). IR (neat film, cm¹): 3480 (m); 3380 (m); 2950(w); 1705 (s); 1610 (s).

4-Chlorosaccharin was prepared by the same method as used for preparing4-methylsaccharin using methyl 6-chloroanthranilate (4.22 g; 22.7 mmol)in acetic acid (22 ml) and conc. HCl (40 ml) and sodium nitrite (1.68 g;24.3 mmol) in water (7 ml) to prepare the diazonium salt which was addedto cupric chloride dihydrate (1.93 g; 11.4 mmol; 0.5 equiv.) and sulfurdioxide (6.5 g; excess) in acetic acid (30 ml)/water (5 ml). Theresulting sulfonyl chloride was treated with ammonium hydroxide (150 ml)as previously described to afford 3.07 g (62%) of 4-chlorosaccharin as apale yellow solid, mp 245°-246° C. ¹ H nmr (300 MHz, CD₃ CN): 7.918 (1H,dd, J=7.39, 1.91 Hz); 7.865 (1H, t, J-7.52 Hz); 7.829 (1H, br d, J=7.30Hz). IR (KBr, CM¹): 3570 (s); 3520 (s); 2950 (s,b); 1735 (s); 1630 (m).FDMS: m/e 217 (M⁺).

2-Hydroxymethyl-4-chlorosaccharin was prepared in the same manner as2-hydroxymethyl-4-methylsaccharin, in Example 1, from 4-chlorosaccharin(1.00 g; 4.60 mmol) and formalin (37%; 3.22 ml; excess). All attempts tocrystallize the viscous oily product resulted in decomposition to thestarting material, and the product was thus used in the next stepwithout characterization.

2-Acetoxymethyl-4-chlorosaccharin was prepared in the same manner asused for 2-acetoxymethyl-4-methylsaccharin, in Example 1, from the crude2-hydroxymethyl-4-chlorosacharin (0.34 g; 1.4 mmol) and acetic anhydride(2.5 ml) with 2 drops of sulfuric acid. In this case, after isolation,the product was purified by filtration through a pad of silica gel andelution with 1:1 ether:hexane to afford2-acetoxymethyl-4-chlorosaccharin (35 mg, 95% yield) as a white solid,mp 138°-142° C. ¹ H nmr (300 MHz, CDCl₃): 7.921 (1H, dd, J=6.54, 2.63Hz); 7.874 (1H, t, J=7.98 Hz); 7.842 (1H, dd, J=6.70, 2.20 Hz); 5.869(2H, s); 2.172 (3H, s). IR (KBr, CM¹): 1745 (s); 1735 (m, shoulder);1575 (w). Comb. anal.:

Theor C, 41,46; H, 2.78; N, 4.83;

Found C, 41.17; H, 2.81; N, 4.75.

EXAMPLE 3

Crude 2-hydroxymethyl-4-chlorosaccharin, from Example 2, (609 mg; 2.46mmol max) was admixed with diethyl ether (5 ml), and thionyl chloride (3ml; excess) was added. The resulting mixture was heated to effectcomplete solution, stirred at room temperature overnight, diluted withether (20 ml) and filtered through a pad of celite topped with sand andeluted with ether. Removal of the solvent afforded 430 mg of crudechloromethyl derivative. A portion (225 mg) was removed for furtherreactions. The remainder (205 mg) was flash chromatographed on silicagel and eluted with 40% ether/pentane to provide 137 mg of2-chloromethyl-4-chlorosaccharin, mp 135°-136° C. ¹ H nmr (300 MHz,CDCl₃): 7.925 (1H, dd, J=6.62, 2.26 Hz); 7.882 (1H, t, J=8.18 Hz); 7.846(1H, dd, J=7.42, 2.36 Hz); 5.561 (2H, s). IR (KBr, CM¹): 3090 (w); 3050(w); 1750 (s); 1575 (m). FDMS: m/e 265 (M⁺).

EXAMPLE 4

The chloromethyl derivative prepared in Example 3 (225 mg; 0.85 mmol)and sodium 1-phenyl-5-mercapto-1H-tetrazole (200 mg; 1.01 mmol; 1.2equiv.) were dissolved in acetone (5 ml) to give a tan solution. Afterabout 10 minutes a precipitate was observed, and after stirringovernight at room temperature no 2-chloromethyl-4-chlorosaccharin waspresent by tlc analysis. The reaction mixture was poured into water andextracted with MDC (3×25 ml). The combined extracts were dried (Na₂SO₄), concentrated and the residue flash chromatographed on silica geland eluted with 1:1 ether:hexane. The major spot was collected to afford122 mg of 4-chloro-2-(1-phenyl-1H-tetrazol-5-ylthiomethyl)saccharin as awhite solid, mp 175°-177° C. ¹ H nmr (300 MHz, CDCl₃): 7.813 (3H, m);7.515 (5H, s); 5.710 (2H, s). IR (Kbr, cm¹): 3080 (w); 1740 (s); 1590(w). FDMS: m/e 407 (M⁺); 230 (M⁺ -PMT); 178 (1%, PMT).

EXAMPLE 5

The chloromethyl derivative prepared as in Example 3, (337 mg crude;maximum 1.27 mmol) was dissolved (to the extent possible) in acetone (10ml). Sodium 1-phenyl-5-mercapto-1H-tetrazole (304 mg; 1.52 mmol; 1.2equiv.) was added, and the reaction mixture was stirred at roomtemperature for 3 days. The mixture was diluted with MDC (50 ml), washedwith water (3×25 ml), dried (Na₂ SO₄), concentrated and filtered througha pad of silica gel (1:1 ether:hexane elution). The material thusobtained was chromatographed on flash silica gel and eluted with 1:1ether:hexane to afford 44 mg (8.5%) of4-chloro-2-(4-phenyl-5-thioxotetrazolin-1-ylmethyl)saccharin mp158°-162° C. ¹ H nmr (300 MHz, CDCl₃): 7.981 (1H, d, J=7.12 Hz); 7.95(2H, m); 7.887 (1H, t, J=6.74 Hz); 7.864 (1H, d, J=7.32 Hz); 7.567 (3H,m); 6.392 (2H, s). IR (KBr, CM¹): 1745 (s); 1185 (s). FDMS: m/e 407(M⁺); 230 (M⁺ -PMT).

EXAMPLE 6

A mixture of 2-(chloromethyl)saccharin (0.98 g, 4.2 mmol),1-(3-acetamidophenyl)-5-mercapto-1H-tetrazole (1 g, 4.2 mmol) andpotassium bicarbonate (0.84 g, 8.4 mmol) in methyl ethyl ketone (50 ml)was heated at 50° C. under nitrogen overnight. The reaction mixture wascooled, poured into dilute HCl ice water (300 ml.), and the water wasdecanted from the semi-solid which solidified on trituration with hotethyl acetate. The resultant white solid was recrystallized fromacetonitrile (MeCN) with charcoaling, to afford 0.82 g of2-[1-(3-acetamidophenyl)-1H-tetrazol-5-ylthiomethyl]saccharin as smallwhite needles, mp 195°-196° C. decomp. ¹ H nmr (90 MHz, CDCl₃):2.05 (3H,s); 5.65 (2H, s). FDMS: m/e 430 (M⁺).

Theor C, 47.43; H, 3.28; N, 19.52;

Found C, 47.02; H, 3.27; N, 19.53.

EXAMPLE 7

A mixture of 2-(bromomethyl)saccharin (2.7 g, 9.8 mmol),1-(3-heptanamidophenyl)-5-mercapto-1H-tetrazole (3 g, 9.8 mmol) andpotassium carbonate (3.4 g., 24.5 mmol) was heated under reflux inmethyl ethyl ketone (50 ml) under nitrogen for 1 hour. The mixture wascooled and poured into a sodium bicarbonate/ice solution. The waterlayer was decanted from the resultant white semi-solid. The semi-solidwas washed with water, then dissolved in hot acetonitrile, the solutiontreated with activated charcoal and filtered. The filtrate was freed ofsolvent under vacuum, and the resultant solid was chromatographed(silica gel-95:5 CH₂ Cl₂ :acetone) to give a clear oil. The oil wascrystallized from hot ethanol to afford 1.6 g of2-[1-(3-heptanamidophenyl)-1H-tetrazol-5-ylthiomethyl]saccharin as awhite solid, mp 146°-147.5° C. ¹ H nmr (90 MHz, CDCl₃): 5.65 (2H, s).FDMS: m/e 500 (M⁺).

Theor C, 52.79; H, 4.83; N, 16.79;

Found C, 52.44; H, 4.75; N, 16.64.

EXAMPLE 8

A mixture of 2-(bromomethyl)saccharin (3 g, 10.8 mmol) and the sodiumsalt of 5-mercapto-1-methyl-1H-tetrazole (1.49 g, 10.8 mmol) was heatedunder reflux in methyl ethyl ketone (75 ml) for 2 hours. The reactionmixture was cooled, poured into dilute sodium bicarbonate/ice solutionand extracted with MDC (2×'s). The combined organic extracts were dried(Na₂ SO₄) and freed of solvent under vacuum. The crude product waschromatographed (silica gel-95:5 CH₂ Cl₂ : ether), and the resultant oilwas crystallized from hot isopropanol to afford 2.7 g (80%) of2-(1-methyl-1H-tetrazol-5-ylthiomethyl) saccharin as a white solid, mp106°-110° C. ¹ H nmr (90 MHz, CDCl₃):5.55 (2H, s). FDMS: m/e 311 (M⁺).

Theor C, 38.58; H, 2.91; N, 22.49;

Found C, 38,53; H, 2.79; N, 22.60.

EXAMPLE 9

A mixture of 2-(chloromethyl)saccharin (3 g, 12.9 mmol),1-cyclohexyl-5-mercapto-1H-tetrazole (2.37 g, 12.9 mmol) and potassiumcarbonate (4.45 g, 32.2 mmol) was heated under reflux in methyl ethylketone (50 ml) for 1 hour. The reaction mixture was cooled, poured intodilute sodium bicarbonate/ice solution and extracted twice with ethylacetate. The combined organic extracts were washed with water, dried(Na₂ SO₄) and freed of solvent under vacuum. Chromatography (silica gel;MDC) afforded 2 g of2-(1-cyclohexyl-1H-tetrazol-5-ylthiomethyl)saccharin as a white foamthat was crystallized from hot cyclohexane, mp 103°-105° C. ¹ H nmr (90MHz, CDCl₃):5.65 (2H, s). FDMS: m/e 379 (M⁺).

Theor C, 47.48; H, 4.52; N, 18.46;

Found C, 47.84; H, 4.61; N, 18.36.

EXAMPLE 10

A mixture of m-chloroperbenzoic acid (0.43 g, 2.67 mmol) and2-(1-phenyl-1H-tetrazol-5-ylthiomethyl)saccharin (1 g, 2.67 mmol) in MDCwas stirred at room temperature for 24 hours. TLC (95:5 CH₂ Cl₂ : ether)revealed the presence of starting sulfide. Additional peracid (0.2 g)was added and the mixture stirred for an additional 2 days. The reactionmixture was washed with sodium bicarbonate solution, dried (Na₂ SO₄) andfreed of solvent under vacuum. Chromatography (silica gel-95:5 CH₂ Cl₂:ether) afforded a foam that was crystallized from ether to afford 0.52g of 2-(1-phenyl-1H-tetrazol-5-ylsulfinylmethyl)saccharin as a whitesolid, mp 161°-162° C. ¹ H nmr (90 MHz, CDCl₃):5.5-6.0 (2H, q). FDMS:m/e 196 (M⁺ -PMT), 389 (M⁺).

Theor C, 46.27; H, 2.85; N, 17.98;

Found C, 46.00; H, 2.83; N, 17.76.

EXAMPLE 11

A mixture of 2-bromomethyl-5-nitrosaccharin (2 g, 6.2 mmol) and1-phenyl-5-mercapto-1H-tetrazole, sodium salt in methyl ethyl ketone (40ml)/DMF (10 ml) was heated under reflux for 2 hours. The reactionmixture was cooled and poured into a dilute sodium bicarbonate/icesolution. The resultant white solid, isolated by filtration, was washedwith water and air dried. The compound was sonicated with 50:50MDC:acetone and filtered to remove soluble impurities. The remainingsolid was recrystallized from 2:1 acetonitrile: ethanol to afford 1.5 gof 5-nitro-2-(1-phenyl-1H-tetrazol-5-ylthiomethyl)saccharin as an offwhite solid, mp 189°-190° C. ¹ H nmr (90 MHz, DMSO-d₆) :5.75 (2H, s).FDMS: m/e 418 (M⁺).

Theor C, 43.06; H, 2.41; N, 20.09;

Found C, 42.29; H, 2.43; N, 20.13.

EXAMPLE 12

A mixture of m-chloroperbenzoic acid (2.2 g, 12.8 mmol) and2-(phenylsulfinylmethyl) saccharin (3.75 g, 11.6 mmol) in MDC (50 ml)was stirred at room temperature for 2 hours. An additional spatula ofperacid was added, and stirring was continued for an additional 1 hour.m-Chlorobenzoic acid was removed by filtration and the solid was washedwith a small amount of MDC. The filtrate was washed with sodiumbicarbonate solution, dried (Na₂ SO₄) and freed of solvent under vacuum.The resultant solid was recrystallized from 50:50 ethanol:acetonitrileto afford 2-(phenylsulfonylmethyl)saccharin as a white solid, mp169°-171° C. ¹ H nmr (90 MHz, DMSO-d₆, CDCl₃):5.15 (2H, s). FDMS: m/e196 (M⁺ -PMT).

Theor C, 49.84; H, 3.29; N, 4.15;

Found C, 49.92; H, 3.24; N, 4.13.

EXAMPLE 13

A mixture of m-chloroperbenzoic acid (0.9 g, 5.37 mmol) and2-(2-pyrimidylthiomethyl)saccharin prepared by procedures similar tothose of Examples 9 and 11 (1.5 g, 4.8 mmol) in MDC (75 ml) was stirredovernight at room temperature. The reaction mixture was washed withsodium bicarbonate solution, dried (Na₂ SO₄) and freed of solvent undervacuum. Part of this crude product (0.5 g) was saved for directconversion to the sulfone; the remaining material was chromatographed(silica gel-95:5 CH₂ Cl₂ :acetone). Recrystallization fromethanol:acetonitrile afforded 0.95 g of2-(2-pyrimidylsulfinylmethtyl)saccharin as white crystals, mp 197°-198°C. decomp. ¹ H nmr (90 MHz, CDCl₃, DMSO-d₆) :5.1-5.5 (2H, q).

Theor C, 44.57; H, 2.81; N, 13.00;

Found C, 44.67; H, 2.84; N, 12.97.

EXAMPLE 14

A mixture of m-chloroperbenzoic acid (0.4 g, 2.3 mmol) and the sulfoxideprepared in Example 13 (0.75 g, 2.3 mmol) in MDC (50 ml) was stirred atroom temperature with TLC (95:5 MDC:acetone) monitoring. After 2 hours,some of the starting sulfoxide still remained; an additional spatula ofperacid was added and the reaction was stirred overnight. Methylenechloride (100 ml) was added and the mixture was washed with sodiumbicarbonate solution. The organic layer was dried (Na₂ SO₄) and thesolvent was removed under vacuum. Recrystallization of the residue fromacetonitrile:ethanol afforded 0.95 g of2-(2-pyrimidylsulfonylmethyl)saccharin as a white solid, mp 225°-227° C.decomp. ¹ H nmr (90 MHz, DMSO-d₆):5.78 (2H, s). FDMS: m/e 196 (M⁺ -PMT),339 (M⁺).

Theor C, 42.47; H, 2.67; N, 12.38;

Found C, 42.20; H, 2.62; N 12.46.

EXAMPLE 15

A mixture of 2-(chloromethyl)saccharin (3 g, 12.9 mmol) and sodiump-nitrophenoxide (2.55 g, 12.9 mmol) in THF (50 ml) was heated overnightat 50° C. and then refluxed for 45 minutes. The reaction mixture wascooled, poured into a dilute sodium bicarbonate/ice solution andextracted twice with ethyl acetate. The combined organic extracts werewashed with sodium bicarbonate solution and water, dried (Na₂ SO₄), andtaken to dryness in vacuo. Chromatography (silica gel; MDC) afforded anoil that was crystallized from hot cyclohexane/ether. The resultantsolid was recrystallized from ethanol to afford 0.92 g of2-(4-nitrophenoxymethyl)saccharin as white shiny platelets, mp 162°-164°C. ¹ H nmr (90 MHz, CDCl₃, DMSO-d₆):5.95 (2H, s). FDMS m/e 334 (M⁺).

Theor C. 50.30; H, 3.02; N, 8.38;

Found C, 50.06; H, 2.91; N, 8.28.

EXAMPLE 16

5-Nitro-2-(1-phenyl-1H-tetrazol-5-ylthiomethyl)saccharin (4 g, 9.56mmol) (Example 11) was dissolved in THF (250 ml) and placed in a Parrshaker bottle. Two spatulas of 10% palladium-on-charcoal catalyst wereadded under nitrogen, and the mixture was shaken under hydrogen (55 psi)for 2.5 days. The reaction mixture was filtered through Celitediatomaceous earth and filtrate mixed with water and extracted with MDC.The organic layer was dried (Na₂ SO₄), freed of solvent under vacuum,and the resultant yellow foam was sonicated with warm ethanol, cooledand filtered. The desired 5-aminosaccharin derivative, 0.5 g, wasisolated as a cream colored solid. FDMS: m/e 388 (M⁺).

A mixture of the above 5-aminosaccharin derivative (0.5 g, 1.29 mmol)and 3,3-diphenylpropanoyl chloride (0.315 g, 1.29 mmol) in acetonitrile(50 ml) was heated under reflux for 2.5 hours. TLC (95:5 methylenechloride:acetone) analysis revealed the presence of some starting amine.A small additional amount of acid chloride was added, refluxing wascontinued for an additional 1.5 hours and the reaction mixture cooledand poured into ice water (400 ml). After 30 minutes, the mixture wasfiltered, and the resultant tan colored solid was washed with water andair dried. Chromatography on silica gel (95:5 MDC:ether) produced a foamthat was crystallized from hot ethanol to yield 0.68 g of5-(3,3-diphenylpropionamido)-2-(1-phenyl-1H-tetrazol-5-ylthiomethyl)saccharinas a white solid, mp 92°-93° C. decomp. FDMS: m/e 596 (M⁺). ¹ H nmr (90mHz, CDCl₃):3.25 (1H, d); 4.8 (2H, t); 5.6 (2H, s); 6.9-8.2 (m, Ar). NMRalso revealed approximately two ethanol molecules of crystallization:1.25 (t); 3.7 (q). Comb. anal.:

Theor for C₃₀ H₂₄ N₆ O₄ S₂ +2C₂ H₅ OH: C, 59.28; H, 5.27; N, 12.2;

Found: C, 58.09; H, 5.15; N, 12.09.

EXAMPLE 17

Methyl 2-chloro-2-phenylthioacetate was prepared as reported in theliterature: I. Fleming and J. Iqbal, Tetra. Lett., 24, 327 (1983); M.Campbell, et al., Tetra. Lett., 21, 3305 (1980).

Saccharin (10 g, 54.6 mmol) was dissolved in ethanol (500 ml) withslight warming. Thallous ethoxide (13.6 g, 54.6 mmol) was addeddropwise, and the resultant heterogeneous mixture was stirred at roomtemperature for 2 hours, then cooled, filtered and the solid washed withcold ethanol. The greyish white, crystalline solid was dried undervacuum in a desiccator to yield 19.4 g (92%) of the thallium salt ofsaccharin.

A mixture of the thallium salt of saccharin (1.78 g, 4.6 mmol) andmethyl 2-chloro-2-phenylthioacetate (1 g, 4.6 mmol) in DMF (25 ml) wasstirred at 60° C. for 7 hours. The mixture was cooled and poured intoice water (400 ml). After 30 minutes, the mixture was filtered, and thesolid was washed with water and air-dried. Chromatography on silica(MDC) afforded a clear oil that was crystallized from hot ethanol toyield 0.87 g (51%) of white needles of methyl2-phenylthio-2-(2-saccharinyl)acetate, mp 144°-146° C. ¹ H nmr (90 MHz,CDCl₃): 3.8 (3H, s); 5.95 (1H, s); 7.2-8.15 (9H, m). FDMS: m/e 363 (M⁺).

A solution of methyl 2-phenylthio-2-(2-saccharinyl) acetate (2 g, 5.5mmol) and sulfuryl chloride (0.74 g, 5.5 mmol) in MDC (50 ml) wasstirred at room temperature for 2 hours. Solvent was removed undervacuum, and the yellow oil was crystallized from warm ethanol to give0.94 g of product. NMR revealed greater than 50% starting material. Anadditional amount of starting material (1 g, 2.75 mmol) was added to thecrude product mixture and it was redissolved in methylene chloride.Sulfuryl chloride (0.5 ml) was again added and the mixture was stirredat room temperature for about 12 hours. Work up as above afforded 0.66 gof crude methyl 2-chloro-2-(2-saccharinyl)acetate that was usedimmediately in the next step.

A mixture of this chloride (0.66 g crude mixture) and1-phenyl-5-mercapto-1H-tetrazole in the form of the sodium salt (0.44 g,2.2 mmol) was heated under reflux in methyl ethyl ketone (25 ml) for 4hours. After stirring at room temperature for 2 days, the reactionmixture was poured into ice water. The tan solid isolated by filtrationwas washed with water and air-dried. Chromatography on silica gel (MDC)yielded an off-white foam that was crystallized from ethanol to yield0.36 g of methyl2-(1-phenyl-1H-tetrazol-5-ylthio)-2-(2-saccharinyl)acetate as a whitecrystalline solid, mp 160°-162° C. ¹ H nmr (90 MHz, CDCl₃):3.8 (3H, s);7.05 (1H, s); 7.4-8.1 (9H, m). FDMS: m/e 431 (M⁺).

Theor for C₁₇ H₁₃ N₅ O₅ S₂ : C, 47.33; H, 3.04; N, 16.23;

Found: C, 47.15; H, 3.09; N, 16.30.

EXAMPLE 18

To a suspension of 6.0 g (0.03 mmol) of cuprous iodide in 100 ml of THFwas added 25 ml of dimethyl sulfide, and the resulting yellow solutionwas cooled to -78° C. and treated dropwise with a solution of 23 ml(0.06 mmol) of a 3.0M solution of phenyl magnesium bromide in diethylether. The resulting pale yellow-orange solution was stirred at -78° C.under nitrogen for one hour and then treated with 3.02 g (0.03 mol) of2-cyclohexenone in 10 ml of THF. The resulting mixture was allowed towarm to 0° C. over a two hour period, recooled to -78° C., treated with15 ml of hexamethylphosphoramide, stirred for thirty minutes, treatedwith 8.0 g (0.09 mmol) of methyl cyanoformate and allowed to warm toambient temperature overnight. The reaction mixture was poured into 100ml of 2N hydrochloric acid, and the organic phase was separated and theaqueous phase back extracted with MDC. The combined organic extractswere taken to dryness in vacuo, and the residue triturated withsaturated ammonium chloride, then with water, then with brine and takento dryness once again to give 3.2 g of methyl 2-phenylcyclohexan-6-onecarboxylate as an oil.

The latter (3.0 g, 0.013 mmol), 4.8 g (0.039 mmol) of benzyl mercaptanand 1.0 g of Amberlyst®-15 resin (Rohm and Haas) in chloroform washeated under reflux for twenty hours, the mixture treated with anadditional 1.5 g of the resin and heated for an additional four hours.The mixture was then cooled to ambient temperature, filtered, thefiltrate taken to dryness in vacuo, the residue triturated with hexaneand the solid collected by filtration to give 0.85 g (19%) of a mixtureof methyl 2-benzylthio, 6-phenylcyclohex-2-ene carboxylate and methyl2-benzylthio-6-phenylcyclohex-1-ene carboxylate, 0.6 g (0.0018 mol) ofwhich was heated with 2.0 g of 2,3-dichloro-5,6-dicyanobenzoquinone in25 ml of toluene with stirring under nitrogen for twenty-four hours. Themixture was filtered through a pad of silica gel, eluting with 2:1MDC:hexane and the eluate taken to dryness to give 0.3 g (67%) of methyl2-benzylthio-6-phenylbenzoate.

The latter 0.52 g (0.0016 mmol) dissolved in 10 ml of MDC was dilutedwith 20 ml of acetic acid and 5 ml of water, the mixture cooled to -10°C., and chlorine gas was bubbled through the mixture until theexothermic reaction subsided. The mixture was then stirred for tenminutes and taken to dryness in vacuo to give 0.41 g (85%) of methyl2-chlorosulfonyl-6-phenylbenzoate which was dissolved in 10 ml of THFand added to 25 ml of a solution of concentrated ammonium hydroxidewhile cooling in an ice/acetone bath. The reaction mixture was extractedwith MDC, the organic phase discarded, and the aqueous layer acidifiedto pH 1 with concentrated hydrochloric acid and extracted with MDC. Theorganic extracts, on washing with brine, drying and evaporation todryness, afforded 0.33 g (97%) of 4-phenylsaccharin.

Following a procedure similar to that described in Example 21, thelatter (0.33 g, 0.0012 mol) was reacted with 0.3 g (0.0019 mol) ofchloromethyl phenyl sulfide in 15 ml of toluene in the presence of 0.08g (0.0025 mol) of tetrabutylammonium bromide and the product,2-phenylthiomethyl-4-phenylsaccharin (0.48 g, 100%), treated withsulfuryl chloride in MDC to give 0.36 g (95%) of2-chloromethyl-4-phenylsaccharin.

EXAMPLE 19

A solution of 2.2 g (0.0071 mol) of 2-(phenylchloromethyl)saccharin and1.4 g (0.0071 mol) of the sodium salt of 1-phenyl-5-mercaptotetrazole in30 ml of DMF was heated at 55° for three and one half hours, thenstirred at ambient temperature for about sixteen hours and poured intoice water containing dilute sodium bicarbonate. The solid whichseparated was collected, washed with water, air dried andchromatographed on silica gel, eluting with 98:2 MDC: diethyl ether, togive 2 g (63%) of2-(1-phenyl-1H-tetrazol-5-ylthiophenylmethyl)saccharin, mp 192°-193° C.

EXAMPLE 20

A solution of 4.53 g (0.022 mol) of the sodium salt of saccharin and 5 g(0.022 mol) of 1-phenyl-4-chloromethyltetrazolin-5-thione in 50 ml ofDMF was heated at 1300° for four hours, then cooled and poured into icewater. The solid which separated was collected, washed with water, driedand chromatographed on silica gel, eluting with MDC, to give 4.8 g (58%)of 2-(1-phenyl-5-thioxotetrazolin-4-ylmethyl)saccharin, mp 140°-142° C.

EXAMPLE 21

A mixture of 3.27 g (0.012 mol) of 4-bromosaccharin [Japanese Pat.Publcn. 58/79,034, published May 12, 1983; C.A. 100, 7773w (1984)], 1.63g (0.015 mol) of potassium t-butoxide, 0.39 g (0.0012 mol) oftetrabutylammonium bromide and 3.0 ml (0.022 mol) of chloromethyl phenylsulfide in 100 ml of toluene was heated under reflux under a nitrogenatmosphere for eight hours and then at ambient temperature for aboutsixteen hours. The reaction mixture was then cooled, diluted with ethylacetate and the organic layer washed with bicarbonate, water and brineand then dried over magnesium sulfate and taken to dryness in vacuo. Theresidual solid was recrystallized from toluene-hexane to give 3.86 g(84%) of 4-bromo-2-phenylthiomethylsaccharin, mp 174.5°-178° C.

To a solution of the latter (3.27 g, 0.0085 mol) in 85 ml of MDC wasadded, dropwise with stirring, 1.02 ml (0.0127 mol) of sulfurylchloride. The mixture was stirred at ambient temperature for an hour anda half, concentrated in vacuo and the residue triturated with hexane andfiltered to give 2.61 g of crude product which was recrystallized fromtoluene-hexane to give 2.24 g (85%) of 2-chloromethyl-4-bromosaccharin,mp 157°-159° C.

EXAMPLE 22A

To a solution of 8.0 ml (0.053 Mol) of tetramethylethylenediamine(TMEDA) in 350 ml of THF at -70° C, was added 42 ml (0.055 mol) of a1.3M solution of s-butyl lithium in hexane and the mixture was stirredfor fifteen minutes. To the solution was added dropwise with stirring asolution of 10.36 g (0.050 mol) of 2-methoxy-N,N-diethylbenzamide in 150ml of THF while maintaining the temperature at -60° C. or below andsulfur dioxide then bubbled into the reaction mixture, keeping thereaction temperature below -50° C. until the reaction mixture was acidto wet litmus paper. The mixture was then stirred at ambient temperaturefor two hours, diluted with 450 ml of hexane, and the solid materialwhich had separated was collected, dissolved in 200 ml of water and themixture treated with 65 g of sodium acetate, and 21.5 g (0.19 mol) ofhydroxylamine-O-sulfonic acid was added in portions with stirring. Thewhite solid which separated was collected and dried to give 7.04 g (49%)of 2-aminosulfonyl-6-methoxy-N,N-diethylbenzamide, mp 190°-194.5° C.

A mixture of the product (4.3 g, 0.015 mol) in 75 ml of dioxane and 25ml of concentrated hydrochloric acid was heated on a steam bath for 70hours, then cooled, concentrated in vacuo, diluted with water and iceand rendered strongly basic with concentrated sodium hydroxide.Extraction of the mixture with MDC and isolation of the product from theorganic extracts afforded 1.29 g (40%) of 4-methoxysaccharin. In analternative, and preferred, procedure, cyclization of2-aminosulfonyl-6-methoxy-N,N-diethylbenzamide to 4-methoxysaccharin in65% yield was carried out in refluxing glacial acetic acid for six and ahalf hours.

Following a procedure similar to that described in Example 21 above,1.14 g (0.0053 mol) of the latter was reacted with 1.31 ml (0.0097 mol)of chloromethyl phenyl sulfide in toluene in the presence of 0.72 g(0.0064 mol) of potassium t-butoxide and 174 mg (0.00054 mol) oftetrabutylammonium bromide to give 1.23 g (69%) of4-methoxy-2-phenylthiomethylsaccharin, mp 152.5°-154.5° C. (from ethylacetatehexane), 1.02 g (0.003 mol) of which was treated with 0.36 ml(0.0045 mol) of sulfuryl chloride in MDC to give 282 mg (36%) of2-chloromethyl-4-methoxysacchar in, mp 169°-174° C.

EXAMPLE 22B

To a solution of 4.74 ml (0.031 mol) of tetramethylethylenediamine in300 ml of THF (passed through alumina prior to use) was added 5.8 g(0.03 mol) of 2-ethyl-N,N-diethylbenzamide. The solution was cooled to-78° C. and treated with a solution of 34.9 ml (0.031 mol) of a 0.9Msolution of s-butyl lithium in cyclohexane. When addition was complete,the mixture was stirred for twenty minutes and then treated with asolution of 3.2 ml (0.04 mol) of ethyl iodide while maintaining thetemperature at -78° C. The temperature was then allowed to rise toambient temperature and the mixture stirred for about sixteen hours andthen poured into water. The resulting oil was separated andchromatographed on silica gel, eluting with 10% ethyl acetate/hexane togive 2.86 g (43%) of 2-sec.-butyl-N,N-diethylbenzamide as a yellow oil.

Following a procedure similar to that described in Example 22A above thelatter (10.45 g, 0.045 mol), dissolved in 70 ml of THF, was added to asolution of 39.2 ml (0.047 mol) of a 1.2M solution of s-butyl lithium incyclohexane and 7.1 ml (0.047 mol) of tetramethylethylenediamine in 250ml of THF while maintaining the temperature at -78° C. When addition wascomplete the mixture was stirred for an additional one half hour at -78°C. and then treated with sulfur dioxide at -70° C. and then allowed towarm to room temperature. The mixture was taken to dryness in vacuo, andthe residue was dissolved in water and added with stirring to a coldsolution of 15.2 g (0.134 mol) of hydroxylaminesulfonic acid and 15.4 ml(0.134 mol) of 35% sodium hydroxide to give 10.1 g (72%) of2-aminosulfonyl-6-sec. -butyl-N,N-diethylbenzamide.

The latter (6.83 g, 0.22 mol) was dissolved in 100 ml of glacial aceticacid and the solution heated under reflux for thirteen hours and thentaken to dryness. The residue was triturated with diethyl ether andcollected by filtration to give 5.7 g (83%) of the diethylammonium saltof 4-sec.-butylsaccharin.

The latter (3.0 g, 0.0096 mol), on reaction with 1.13 ml (0.012 mol) ofchloromethyl phenyl sulfide in toluene, afforded 3.47 g (100%) of2-phenylthiomethyl-4-sec.-butylsaccharin.

Reaction of the latter (3.2 g, 0.0097 mol) with 2.3 ml (0.029 mol) ofsulfuryl chloride in 20 ml of MDC afforded 2.4 g (87%) of2-chloromethyl-4-sec.-butylsaccharin.

EXAMPLE 22C

To a solution of 9.3 ml (0.058 mol) of tetramethylethylenediamine in 340ml of THF at -78° C. was added 52 ml of a 1.1M solution (0.057 mol) ofs-butyl lithium in THF. The solution was then treated with a solution of11.37 g (0.052 mol) of 2-propyl-N,N-diethylbenzamide in 75 ml of THF at-78° C. and the solution stirred for fifteen minutes and then treatedwith a solution of 8.3 ml of (0.104 mol) of ethyl iodide in THF. Thesolution was stirred for an hour and a half at -78° C. and then quenchedby the addition of saturated ammonium chloride added dropwise at -78° C.The mixture was then allowed to warm to ambient temperature, dilutedwith diethyl ether, washed first with dilute hydrochloric acid, thenwith water, then with saturated sodium bicarbonate, then with brinedried and taken to dryness to give 12.91 g of crude product which waschromatographed on silica gel, eluting with 10% ethyl acetate/hexane togive 3.23 g (25%) of 2-(3-pentyl)-N,N -diethylbenzamide as a yellow oil.

Following a procedure similar to that described in Example 22A above,the latter (3.05 g, 0.0115 mol) in THF was reacted with 10.5 ml (0.126mol) of a 1.2M solution of s-butyl lithium in THF in the presence of 2.1ml (0.014 mol) of tetramethylethylenediamine. The resulting lithium saltwas then reacted first with sulfur dioxide and then with sodiumhydroxylaminesulfonate to give 1.97 g (52%) of2-aminosulfonyl-6-(3-pentyl)-N,N-diethylbenzamide as pale yellowcrystalls, mp 118°-120° C. (soft 102°), 1.84 g (0.0056 mol) of which wascyclized in 22 ml of refluxing glacial acetic acid to give 1.28 g (70%)of the diethylammonium salt of 4-(3-pentyl) saccharin, mp 107.5°-109.5°C.

The latter (0.0037 mol), on reaction with 0.74 ml (0.0055 mol) ofchloromethyl phenyl sulfide in the presence of 116 mg (0.0004 mol) oftetrabutylammonium bromide in 45 ml of toluene, afforded 1.93 g of2-phenylthiomethyl-4-(3-peptyl)saccharin as a pale yellow oil, 1.93 g(0.0037 mol) of which, on reaction with 0.59 ml (0.0073 mol) of sulfurylchloride in 37 ml of MDC, afforded 1.2 g of2-chloromethyl-4-(3-pentyl)saccharin as a pale yellow oil.

EXAMPLE 22D-22N

Following a procedure similar to that described above in Example 22A,substituting for the 2-methoxy-N,N-diethylbenzamide used therein anappropriate 2-R₃ -R₄ -substituted-N,N-diethylbenzamide, the following2-halomethyl-4-R₃ -R₄ -substituted saccharins listed in TABLE A wereprepared via the corresponding 2-phenylthiomethylsaccharins. Whereveravailable, the melting point, recrystallization solvent and yield aregiven for each of the 2-unsubstituted saccharins, the2-phenylthiomethylsaccharins and the 2-chloromethylsaccharins in columnsheaded "mp/Solv." and "Yield". In all instances, the intermediate2-phenylthiomethylsaccharins were used directly in the subsequent stepwithout further characterization or purification.

                                      TABLE A                                     __________________________________________________________________________              Sacc.      2-C.sub.6 H.sub.5 SCH.sub.2 -Sacc.                                                      2-ClCH.sub.2 -Sacc.                            Ex.                                                                              R.sub.3 /R.sub.4                                                                     mp/Solv.                                                                             Yield                                                                             mp/Solv.                                                                           Yield                                                                              mp/Solv. Yield                                 __________________________________________________________________________    22D                                                                              H      260-262                                                                              93  --   100  158.0-160.0                                                                            41                                       7-Cl                        i-PrOH                                         22E                                                                              CH(CH.sub.3).sub.2                                                                   177.0-178.0                                                                          88  --   100  96.0-98.0                                                                              20                                       H      MeOH                 i-PrOH-Cyc. hex.                               22F                                                                              CH.sub.3 O                                                                           (a)    64  --   100  190.0-192.0                                                                            76                                       5-CH.sub.3 O                                                               22G                                                                              COOCH.sub.3                                                                          (b)    76  --    65  186.0-187.0                                       H      EtOAc-hex.                                                          22H                                                                              C.sub.2 H.sub.5 O                                                                    (a)    96  --    95  139.0-140.0                                                                            97                                       H                                                                          22I                                                                              (CH.sub.3).sub.2 CHO                                                                        87  --    75  142.5-143.5                                                                            94                                       H                                                                          22J                                                                              CH.sub.3 O                                                                           (a)    94  --    89                                                    6-CH.sub.3 O                                                               22K                                                                              CH(CH.sub.3)--                                                                              83  --   100  --       87                                       (C.sub.2 H.sub.5)                                                             H                                                                          22L                                                                              C.sub.2 H.sub.5                                                                      240-243                                                                              67  --    52  163-168  99                                       5,7-(CH.sub.3 O).sub.2                                                               i-PrOH               hexane                                         22M                                                                              CH(C.sub.2 H.sub.5).sub.2                                                            107.5-109.5                                                                          70  --   100  oil      100                                      H      Me t-Bu                                                                       ether:hex.                                                          22N                                                                              C.sub.6 H.sub.5                                                                      (c)        --   100  --       100                                      H                                                                          __________________________________________________________________________     (a) Isolated and used in the next step as the diethylammonium salt.           (b) The 2unsubstituted-saccharin was prepared by cyclization of dimethyl      3aminosulfonylphthalate in methanol in the presence of a molar equivalent     of sodium methoxide. The phthalate ester was prepared by diazotization of     dimethyl 3aminophthalate, decomposition of the diazonium salt with sulfur     dioxide in the presence of cupric chloride and reaction of the resulting      dimethyl 2chlorosulfonylphthalate with ammonia. (84% yield overall).          (c) See Example 21B for preparation of 2unsubstituted-saccharin.         

EXAMPLE 23

Following a procedure similar to that described in Example 1, reactionof 18.3 g (0.1 mol) of saccharin with 70 ml of 37% formalin in ethanolafforded 3.58 g (70%) of 2-hydroxymethylsaccharin, 25 g (0.117 mol) ofwhich was reacted with 63.3 g (0.234 mol) of phosphorus tribromide indiethyl ether to give 29.8 g (92%) of 2-bromomethylsaccharin, mp155°-157° C.

EXAMPLE 24

To a solution of 4 g (0.0175 mol) of 6-nitrosaccharin in 240 ml ofethanol was added 4.4 g (0.0175 Mol) of thallium ethoxide, and themixture was allowed to stand at room temperature for one hour, cooledfor about 16 hours and the precipitated solid collected and dried togive 7.6 g (100%) of the thallium salt of 6-nitrosaccharin. The productwas suspended in 50 ml of DMF and the mixture treated with 3.07 g(0.0194 mol) of chloromethyl phenyl sulfide, the mixture warmed at about63° C. for five hours, allowed to stand at ambient temperature for about16 hours, and then poured into ice water. The crude product, obtained byfiltration, was stirred in MDC and filtered to remove thallium salts.The filtrate was freed of solvent, and the resultant pale yellow solidwas sonicated with warm ethanol and once again collected and dried togive 4.6 g (75%) of 6-nitro-2-phenylthiomethylsaccharin, mp 161°-163° C.The latter, on reaction with sulfuryl chloride in MDC using theprocedure described above in Example 17 afforded 3.7 g of2-chloromethyl-6-nitrosaccharin.

EXAMPLE 25A

A solution of 49.8 g (0.199 mol) of2-hydroxy-5-(1,1,3,3-tetramethylbutyl)benzoic acid in 200 ml of methanolwas heated to 50° C. and then treated dropwise with about 80 g ofsulfuric acid at a rate to maintain the reaction under reflux. Thereaction mixture was heated under reflux for an additional 11 hours,then cooled and partitioned between water and ethyl acetate. The organiclayer was washed with saturated sodium bicarbonate, then with brine,dried over sodium sulfate and taken to dryness to given 48.6 g (92%) ofmethyl 2-hydroxy-5-(1,1,3,3-tetramethylbutyl)benzoate.

The latter dissolved in 250 ml of DMF was treated first with 40.4 g(0.36 mol) of 1,4-diazabicyclo[2.2.2]octane followed by 33.4 g (0.27mol) of dimethyl thiocarbamoyl chloride and 100 ml of DMF. The reactionmixture was heated at 45° C. for about eight hours, cooled, poured intoice/water and concentrated hydrochloric acid and then extracted withethyl acetate. The combined organic extracts were washed with dilutehydrochloric acid, then with sodium bicarbonate and then with brine,dried and taken to dryness to give 48.2 g (76%) of methyl2-(N,N-dimethylthiocarbamyloxy)-5-(1,1,3,3-tetramethylbutyl)benzoatewhich was heated at 220° C. for 15 hours, then cooled, dissolved intoluene and chromatographed on silica, eluting with 1:9 ethyl acetate:toluene, to give 3.6 g (14%) of methyl2-(N,N-dimethylcarbamylthio)-5-(1,1,3,3-tetramethylbutyl) benzoate.

A solution of the latter (0.025 mol) in 40 ml of MDC was treated, withstirring, with 80 ml of glacial acetic acid, followed by 16 ml of water.The reaction mixture was cooled to 0° C., and chlorine was bubbledthrough the reaction mixture for about five minutes while maintainingthe temperature between 5° and 24° C. The reaction was stirred for anadditional 30 minutes, concentrated in vacuo, and the remaining solutionpoured into ice water. Extraction of the mixture with ethyl acetate andisolation of the product from the combined organic extracts afforded 6.8g (78%) of methyl 2-chlorosulfonyl-5-(1,1,3,3-tetramethylbutyl)benzoate.

The product (9.0 g, 0.026 mol) was dissolved in THF and added to 100 mlof concentrated ammonium hydroxide with cooling in an ice bath. Theresulting solution was stirred for about 16 hours, then concentrated invacuo and the concentrated solution acidified to pH 3 with concentratedhydrochloric acid. The mixture was stirred for several hours, and theseparated solid collected, washed with water and dried to give 9.0 g of5-(1,1,3,3-tetramethylbutyl)saccharin, mp 213°-215° C.

Following a procedure similar to that described in Example 17, 9.0 g(0.30 mol) of the product was reacted with thallium ethoxide in ethanoland the resulting thallium salt reacted with 3.33 g (0.021 mol) ofchloromethyl phenyl sulfide in DMF to give 5.76 g (66%) of2-phenylthiomethyl-5-(1,1,3,3-tetramethylbutyl) saccharin, 3.3 g (0.007mmol) of which was treated with 0.944 g of sulfuryl chloride in MDC togive 1 g (41%) of 2-chloromethyl-5-(1,1,3,3-tetramethylbutyl)saccharin.

EXAMPLE 25B

Following a procedure similar to that described Example 25A above, 15.5g (0.086 mol) of ethyl 2-hydroxy-6-methylbenzoate was reacted with 15.9g (0.129 mol) of N,N-dimethylchlorothiocarbamate in the presence of 19.3g (0.172 mol) of 1,4-diazabicyclo[2.2.2]octane in DMF to give 22.1 g(96%) of ethyl 2-(N,N-dimethylthiocarbamyloxy)-6-methylbenzoate whichwas heated at 220° C. for about 10 hours. The product was purified bychromatography on silica gel in MDC to give ethyl2-(N,N-dimethylcarbamylthio)-6-methylbenzoate as a red-brown oil.

A solution of the latter (22.6 g, 0.0844 mol) in 170 ml of MDC wastreated with 340 ml of glacial acetic acid and 68 ml of water whilecooling in an ice/acetone bath, and chlorine was bubbled through thereaction mixture for 10-15 minutes. The reaction vessel was evacuated toremove excess chlorine and MDC and the mixture poured into water andpartitioned between MDC and water. The organic layer, on drying andevaporation to dryness, afforded 19 g of ethyl2-chlorosulfonyl-6-methylbenzoate, 5 g (0.019 mol) of which was reactedwith concentrated ammonium hydroxide in THF to give 6.1 g (67%) of4-methylsaccharin.

Following a procedure similar to that described in Example 17 above, theproduct (10.1 g, 0.0512 mol) was converted to the thallium salt byreaction with 12.8 g (0.0512 mol) of thallium ethoxide in ethanol andthe thallium salt reacted with 6.7 g (0.0427 mol) of chloromethyl phenylsulfide in DMF to give 6.85 g (50%) of2-phenylthiomethyl-4-methylsaccharin.

Reaction of the latter (6.7 g, 0.021 mol) with sulfuryl chloride in MDCafforded 4.9 g (95%) of 2-chloromethyl-4-methylsaccharin.

EXAMPLE 26A

A mixture of 75 g (0.36 mol) of 3,3-dithiobispropionic acid, 102 ml ofthionyl chloride and a catalytic amount of pyridine was stirred forabout 24 hours and then evaporated to dryness in vacuo. The residue wastreated with MDC and evaporated to dryness again to remove residualthionyl chloride and pyridine to give 87 g (98%) of the correspondingbis acid chloride, 44.8 g (0.18 mol) of which was dissolved in THF andadded dropwise to a solution of 77.16 g (0.72 mol) of benzylamine inTHF. The mixture was stirred for two hours at 40°-45° C., cooled and theprecipitated solid collected, washed with water and dried to give 59 g(84%) of 3,3-dithiobispropionic acid N,N'-dibenzylcarboxamide, mp162°-165° C.

Reaction of 7.0 g (0.018 mol) of the latter with 10.25 g (0.076 mol) ofsulfuryl chloride in MDC gave a mixture of 2-benzyl-2H-isothiazol-3-oneand 5-chloro-2-benzyl-2H-isothiazol-3-one which were largely separatedfrom one another by sonication in MDC (which solubilized most of theformer). The insoluble material was collected by filtration andchromatographed on silica gel with MDC. There was thus obtained5-chloro-2-benzyl-2H-isothiazol-3-one, mp 58°-68° C.

A solution of 10 g (0.044 mol) of the latter in MDC was cooled to 0° C.and the solution treated with 7.6 g (0.044 mol) of 3-chloroperbenzoicacid, the mixture stirred for 10 minutes and then treated with a second7.6 g portion of the perbenzoic acid. The reaction mixture was filtered,the filter washed with MDC and the filtrate washed with saturated sodiumbicarbonate, then with brine, dried over sodium sulfate and taken todryness and the residue chromatographed in MDC on silica gel, theproduct being eluted with 50:50 hexane:MDC, to give 7.15 g (46%) of5-chloro-2-benzyl-2H-isothiazol-3-one-1-oxide.

A solution of 1.1 g (0.0045 mol) of the latter in 8 ml of benzene wastreated with 0.55 g (0.0051 mol) of 2-methoxyfuran and the solutionheated in a pressure bottle at 70° C. for 11/2 hours and then cooled andthe solid collected, washed with benzene and dried to give2-benzyl-7-hydroxy-4-methoxybenzisothiazol-3-one-1-oxide, mp 235°-237°C.

A mixture of the product (1.85 a, 0.006 mol), 2.48 g (0.018 mol) ofpotassium carbonate and 1.70 g (0.012 mol) of methyl iodide in acetonewas heated under reflux for 11/2 hours and then cooled and poured intowater. The solid which separated was collected by filtration, washedwith water and dried to give 1.70 g (89%) of2-benzyl-4,7-dimethoxybenzisothiazol-3-one-1-oxide, 1.13 g (0.0035 mol)of which was oxidized with 1.20 g (0.007 mol) of 3-chloroperbenzoic acidin MDC using the procedure described above to give 1.03 g (88%) of2-benzyl-4,7-dimethoxysaccharin.

A mixture of 2.07 g (0.0062 mol) of the product, 1.37 g (0.02 mol) ofammonium formate and 1.5 g of 10% palladium-on-charcoal catalyst in 80ml of methanol was heated under reflux for one hour, then cooled andfiltered, and the filtrate taken to dryness to give 0.92 g (57%) of theammonium salt of 4,7-dimethoxysaccharin.

A solution of 1.11 g (0.0042 mol) of the ammonium salt was dissolved inDMF, 0.67 g (0.0042 mol) of chloromethyl phenyl sulfide was added, andthe solution heated under reflux for eight hours and then cooled andpoured into ice water. The solid which separated was collected, washedwith water and dried to give 0.50 g (33%) of2-phenylthiomethyl-4,7-dimethoxysaccharin.

Reaction of the latter (0.5 g, 0.0013 mol) with sulfuryl chloride in MDCusing the procedure described above in Example 17 afforded 0.22 g (58%)of 2-chloromethyl-4,7-dimethoxysaccharin.

EXAMPLE 26B and 26C

Following a procedure similar to that described in Example 26A, other2-chloromethylsaccharin derivatives were prepared as follows:

EXAMPLE 26B

Reaction of 5.8 g (0.024 mol) of 5-chloro-2-benzyl-2H-isothiazol-3-onewith 3.76 g (0.0335 mol) of 2-ethoxyfuran afforded 3.05 g (40%) of2-benzyl-4-ethoxy-7-hydroxybenzisothiazol-3-one-1-oxide, 5.7 g of whichwas reacted with 3.6 g (0.0197 mol) of 2-[2-methoxyethoxy]ethyl bromidein the presence of 4.95 g (0.0358 mol) of potassium carbonate in 125 mlof methyl ethyl ketone and 25 ml of DMF to give 7.0 g (93%) of 2-benzyl-4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]benzisothiazol-3-one-1-oxide,which was oxidized as before with 3-chloroperbenzoic acid in MDC to give2-benzyl -4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin. Debenzylationof 6.6 g (0.015 mol) of the latter with 3.34 g (0.053 mol) of ammoniumformate in the presence of 6.4 g of 10% palladium-on-charcoal catalystin methanol afforded the ammonium salt of4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin, which was reacted with2.38 g (0.015 mol) of chloromethyl phenyl sulfide in 100 ml of DMF togive 1.46 g (21%) of2-phenylthiomethyl-4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin, mp73°-75° C. (from isopropanol). Treatment of 1.4 g (0.0029 mol) of theproduct with 0.4 g (0.0029 mol) of sulfuryl chloride in MDC afforded1.16 g (100%) of 2-chloromethyl-4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin.

EXAMPLE 26C

Reaction of 3.03 g (0.01 mol) of2-benzyl-7-hydroxy-4-methoxybenzisothiazol-3-one-1-oxide (Example 26A)with 2.01 g (0.011 mol) of 2-(2-methoxyethoxy)ethyl bromide in methylethyl ketone in the presence of 2 g (0.015 mol) of potassium carbonateafforded 2.58 g (64%) of2-benzyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]benzisothiazol-3-one-1-oxide,which, on oxidation with 1.1 g (0.0063 mol) of 3-chloroperbenzoic acidin MDC, gave 2-benzyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin.Debenzylation of 0.25 g (0.0006 mol) of the product with 0.13 g (0.0021mol) of ammonium formate in methanol in the presence of 0.25 g of 10%palladium-on-charcoal gave 0.21 g (100%) of the ammonium salt of4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin. Reaction of 1.4 g(0.004 mol) of the ammonium salt with 0.63 g (0.004 mol) of chloromethylphenyl sulfide in DMF afforded2-phenylthiomethyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin,which, on reaction with sulfuryl chloride in MDC, afforded 0.53 g (35%)of 2-chloromethyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin.

EXAMPLE 27

A solution of 1.89 g (0.011 mol) of diethylamino sulfur trifluoride(DAST) in 20 ml of MDC was added to a suspension of 2.13 g (0.01 mol) of2-hydroxymethylsaccharin in 25 ml of MDC while maintaining the reactionmixture at -78° C.

The reaction mixture was stirred at -78° C. for one hour, thetemperature was then allowed to slowly rise to ambient temperature andthe mixture stirred for 16 hours and then poured into ice-water. Theorganic layer was separated and washed with water, dried over magnesiumsulfate and taken to dryness to give 2.2 g of product which wasrecrystallized from ethyl acetate to give 1.6 g (74%) of2-fluoromethylsaccharin, mp 96°-98° C.

EXAMPLE 28A

To a solution of 0.5 g (0.0025 mol) of 4-methylsaccharin in THF cooledto -78° C. by a dry ice/acetone bath was added, dropwise with stirring,a solution of 5.2 ml of a 1.3M solution of s-butyl lithium in THF. Themixture was stirred an additional hour at -78° C. and then treated with0.16 ml (0.025 mol) of methyl iodide over a 11/2 hour period. Themixture was stirred for an hour and 45 minutes, quenched in 25 ml of 1Nhydrochloric acid, the reaction mixture rendered basic, the aqueousmixture extracted with chloroform and then acidified and extracted withethyl acetate. The combined organic extracts were washed with 10% sodiumthiosulfate, then with brine, dried over sodium sulfate and taken todryness to give a product, whose PMR spectrum indicated a mixtureconsisting of 74% of 4-ethylsaccharin and 21% of 4,7-dimethylsaccharin.

Following a procedure similar to that described in Example 17 above, thecrude material (0.47 g, 0.022 mol) was reacted with 0.24 ml (0.0028 mol)of chloromethyl phenyl sulfide in toluene in the presence oftetrabutylammonium bromide, and the product chromatographed on silicagel, eluting with MDC, 5 ml fractions being collected. The first 420 mlof eluate were discarded. The next 20 fractions, on evaporation,afforded 0.07 g of material, predominantly the 4,7-dimethylsaccharin,which was set aside. The next 25 fractions afforded 0.37 g of2-phenylthiomethyl-4-ethylsaccharin, which was reacted with sulfurylchloride in MDC to give 0.19 g (66%) of 2-chloromethyl-4-ethylsaccharin.

EXAMPLE 28B

Following a procedure similar to that described in Example 28A 10 g(0.051 mol) of 4-methylsaccharin was reacted with 86 ml (0.10 mol) of a1.18M solution of s-butyl lithium in THF and the resulting solutiontreated with 4.5 ml (0.050 mol) of ethyl iodide to give 10.15 g (89%) of4-propylsaccharin, which on reaction with 5.32 ml (0.056 mol) ofchloromethyl phenyl sulfide in toluene in the presence oftetrabutylammonium bromide afforded a 65% yield of2-phenylthiomethyl-4-propylsaccharin as an oil, 1.8 g (0.0052 mol) ofwhich, on reaction with 1.25 ml (0.016 mol) of sulfuryl chloride in MDCafforded 0.94 g (66%) of 2-chloromethyl-4-propylsaccharin.

EXAMPLE 29

The 0.07 g sample of material obtained in the early fractions from thechromatographic separation described above in Example 28A was reactedwith 0.05 ml of sulfuryl chloride in MDC and the product recrystallizedfrom cyclohexane-ethyl acetate to give 20 mg (51%) of2-chloromethyl-4,7-dimethylsaccharin, mp 107°-108° C.

EXAMPLE 30A-30BK

Following a procedure similar to that described in Example 4 above,substituting for the 2-chloromethyl-4-chlorosaccharin and the sodium1-phenyltetrazole salt used therein, molar equivalent amounts of arespective appropriate 2-halomethyl-4-R₃ -R₄ -substituted saccharin andan appropriate L_(n) R₁ moiety, the following compounds of formula I inTABLE B below were prepared. The identities of the halogen moiety in the2-halomethylsaccharin and the base used to catalyze the reaction, i.e.,either the sodium or thallium salt of the L_(n) R_(l) reactant or theadded basic catalyst, i.e., potassium carbonate, triethylamine (TEA),ethyldiisopropylamine (EDIPA) or sodium methoxide, are given in thecolumn headed "X/Base". The reaction solvent used (DMF, THF, MDC, MEK oracetone) is given in the column headed "Sol.", and the melting point(mp) and the solvent used for recrystallization are given in the columnheaded "mp/From". In TABLE B, and in the other tables which follow,various heterocyclic or other groups, R_(l), are abbreviated as follows:

    ______________________________________                                        tet.                tetrazolyl                                                triaz.              triazolyl                                                 Mor.                morpholinyl                                               thiadiaz.           thiadiazolyl                                              imidaz.             imidazolyl                                                benzthiaz.          benzothiazolyl                                            benzoxaz.           benzoxazolyl                                              ______________________________________                                    

                                      TABLE B                                     __________________________________________________________________________    Ex. R.sub.1 /R.sub.2                                                                        R.sub.3 /R.sub.4                                                                          n/L                                                                              X/Base                                                                             Solv.  mp/From  Yield                       __________________________________________________________________________    30A 1-C.sub.6 H.sub.5 -5-tet.                                                               H           1  Cl   DMF    168-170  67                              H         5-(CH.sub.3).sub.3 CCH.sub.2 C(CH.sub.3).sub.2                                            S  Na Salt     EtOH                                 30B 4-Mor.SO.sub.2 C.sub.6 H.sub.4                                                          H           1  Br   THF    Foams-no mp                              H         H           O  TEA                                              30C 1-(3-NH.sub.2 C.sub.6 H.sub.4)-                                                         H           1  Br   DMF    187-189  66                              5-tet.                                                                        H         H           S  TEA         EtOH--CH.sub.3 CN                    30D 1-(4-HOOCC.sub.6 H.sub.4)-                                                              H           1  Cl   MDC    201-202  14                              5-tet.                                                                        H         H           S  TEA         i-ProH--CH.sub.3 CN                  30E 1-[3,5-(MeOOC).sub.2 -                                                                  H           1  Cl   MEK/DMF                                                                              126-129  42                              C.sub.6 H.sub.3 ]-5-tet.                                                      H         H           S  K.sub.2 CO.sub.3                                                                          EtOH--CH.sub.2 CN                    30F 2-pyrimidinyl                                                                           H           1  Br   MEK    170-172  40                              H         H           S  K.sub.2 CO.sub.3                                                                          EtOH--CH.sub.3 CN                    30G 6-(1-oxophen-                                                                           H           1  Br   DMF    233-234  15                              alenyl)                                                                       H         H           O  TlOEt                                            30H 1-C.sub.6 H.sub.5 -5-tet.                                                               CH.sub.3    1  Cl   Acet.  162-164  89                              H         H           S  Na Salt                                                                            MDC                                         30I 1-C.sub.6 H.sub.5 -2-(1,3,4-                                                            H           1  Br   DMF                                             triaz.)                                                                       H         H           S  TlOEt                                            30J 1-(4-Mor.CH.sub.2 --                                                                    C.sub.2 H.sub.5                                                                           1  Cl   MDC    oil                                      CH.sub.2)-5-tet.                                                              H         H           S  TEA                                              30K 1-(4-Mor.CH.sub.2 --                                                                    H           1  Br   MDC    oil                                      CH.sub.2)-5-tet.                                                              H         H           S  TEA                                              30L 1-C.sub.6 H.sub.5 -5-tet.                                                               C.sub.2 H.sub.5 O                                                                         1  Cl   MEK    94-96    74                              H         7-CH.sub.3 (OCH.sub.2 CH.sub.2).sub.2 O                                                   S  Na Salt                                          30M 1-C.sub.6 H.sub.5 -5-tet.                                                               CH.sub.3 O  1  Cl   MEK    104-106                                  H         7-CH.sub.3 (OCH.sub.2 CH.sub.2).sub.2 O                                                   S  Na Salt                                          30N 3-(pyrido-                                                                              H           1  Br   DMF    198-200  66                              [2,1-c]-s-triaz.                                                              H         H           S  TEA         EtOH--CH.sub.3 CN                    30-O                                                                              4-(3-HOOC.sub.6 H.sub.4)-                                                               H           0  Br   MDC    Dec. 110                                 5-thioxo-1-tet.                                                               H         H           -- TEA         i-PrOH                               30P 5-(CyclohexNH)-                                                                         H           1  Br   DMF    188.5-190.5                                                                            61                              2-(1,3,4-thiadiaz.)                                                           H         H           S  TEA         EtOH                                 30Q 1-(3-pyridyl)-                                                                          H           1  Br   DMF    149.0-150.0                                                                            53                              5-tet.                                                                        H         H           S  TEA         EtOH--CH.sub.3 CN                    30R 4-(3-pyridyl)-                                                                          H           0  Br   DMF    108.0-110.0                                                                             8                              5-thioxo-1-tet.                                                               H         H           -- NaH         EtOAc                                30S 4-(3-CH.sub.3 CONH--                                                                    CH.sub.3    1  Cl   DMF    225-227  42                              C.sub.6 H.sub.4)-5-triaz.                                                     H         H           S  K.sub.2 CO.sub.3                                                                          CH.sub.3 CN                          30T 1-C.sub.6 H.sub.5 -5-tet.                                                               CH.sub.3 O  1  Cl   DMF/MEK                                                                              192-193                                  H         7-CH.sub.3 O                                                                              S  Na Salt                                          30U 1-C.sub.6 H.sub.5 -5-tet.                                                               CH.sub.3 O  1  Cl   DMF    164-165  73                              H         H           S  Na Salt     EtOH--CH.sub.3 CN                    30V 1-C.sub.6 H.sub.5 -5-tet.                                                               Br          1  Cl   DMF    185.5-188.0                                                                            69                              H         H           S  Na Salt     EtOH--CH.sub.3 CN                    30W 2-Me-5-thioxo-                                                                          H           0  Br   CH.sub.3 OH                                                                          133.5-135.0                                                                            15                              1-tet.                                                                        H         H           -- NaOMe       EtOAc-hex                            30X 2-Me-5-tet.                                                                             H           1  Br   CH.sub.3 OH                                                                          182.0-183.0                                                                            17                              H         H           S  NaOMe       EtOAc-hex                            30Y 1-(3-pyridyl)-                                                                          H           1  Cl   DMF    138.5-140.5                                                                            39                              5-tet.                                                                        H         H           S  TEA         EtOH                                 30Z 4-(3-pyridyl)-                                                                          (CH.sub.3).sub.2 CH                                                                       0  Cl   DMF    157.0-159                                                                              11                              5-thioxo-1-tet.                                                               H         H           -- TEA         EtOH                                 30AA                                                                              1-C.sub.6 H.sub.5 -5-tet.                                                               (C.sub.2 H.sub.5).sub.2 CH                                                                1  Cl   DMF    88.0-90.0                                                                              52                              H         H           S  Na Salt     Et.sub.2 O-hex                       30AB                                                                              5-Me-2-(1,3,4-                                                                          H           1  Br   DMF    114-116  75                              thiadiaz.)                                                                    H         H           S  TEA         i-PrOH                               30AC                                                                              1-Me-2-(1,3,4-                                                                          H           1  Br   DMF    187-189  28                              triaz.)                                                                       H         H           S  TEA         EtOH                                 30AD                                                                              2-MeS-5-thioxo-                                                                         H           0  Br   DMF    132-134  68                              4-(1,3,4-thiadiaz.)                                                           H         H           -- TEA         EtOAc-hex                            30AE                                                                              1-C.sub.6 H.sub.5 -5-tet.                                                               C.sub.2 H.sub.5                                                                           1  Cl   DMF    180.0-182.0                                                                            43                              H         H           S  Na Salt     EtOAc-CHCl.sub.3                     30AF                                                                              4-C.sub.6 H.sub.5 -2-                                                                   H           1  Br   DMF    117.0-119.0                                                                            33                              (1,3,5-thiadiaz.)                                                             H         H           S  TEA         i-PrOH                               30AG                                                                              1-C.sub.6 H.sub.5 -5-tet.                                                               H           1  Cl   DMF    166.0-168.0                                                                            30                              H         7-Cl        S  Na Salt     CH.sub.3 CN                          30AH                                                                              5-HS-2-(1,3,4-                                                                          H           1  Br   EtOH   201.0-203.0                                                                            32                              thiadiaz.)                                                                    H         H           S  NaOMe       EtOH                                 30AI                                                                              1-C.sub.6 H.sub.5 -5-tet.                                                               CH.sub.3 O  1  Cl   DMF    158.0-160.0                              H         5-CH.sub.3 O                                                                              S  Na Salt     EtOH                                 30AJ                                                                              4-C.sub.6 H.sub.5 -5-                                                                   (CH.sub.3).sub.2 CH                                                                       0  Cl   DMF    178.0-179.5                                                                            16                              thioxo-1-tet.                                                                 H         H           -- Na Salt     EtOH                                 30AK                                                                              1-C.sub.6 H.sub.5 -5-tet.                                                               (CH.sub.3).sub.2 CH                                                                       1  Cl   DMF    140.0-141.0                              H         H           S  Na Salt     EtOH                                 30AL                                                                              1-C.sub.6 H.sub.5 -5-tet.                                                               n-C.sub.3 H.sub.7                                                                         1  Cl   DMF    109.0-111.0                                                                            24                              H         H           S  Na Salt     EtOH--CH.sub.3 CN                    30AM                                                                              5-CH.sub.3 -2-(1,3,-                                                                    (CH.sub.3).sub.2 CH                                                                       1  Cl   DMF    72-74    74                              4-thiadiaz.)                                                                  H         H           S  TEA                                              30AN                                                                              1-CH.sub.3 -5-tet.                                                                      (CH.sub.3).sub.2 CH                                                                       1  Cl   DMF    137.0-139.0                                                                            51                              H         H           S  TEA         EtOH--H.sub.2 O                      30AO                                                                              1-C.sub.6 H.sub.5 -5-tet.                                                               CH.sub.3 CHC.sub.2 H.sub.5                                                                1  Cl   DMF    120.0-122.0                                                                            52                              H         H           S  Na Salt     EtOAc-hex                            30AP                                                                              1-EtO.sub.2 CCH.sub.2 -                                                                 H           1  Br   DMF    142.0-143.0                                                                            29                              5-tet.                                                                        H         H           S  TEA         MDC-hex                              30AQ                                                                              1-(HOCH.sub.2 CH.sub.2)-                                                                H           1  Br   MDC    148.0-150.0                                                                            88                              5-tet.                                                                        H         H           S  EDIPA                                            30AR                                                                              1-C.sub.6 H.sub.5 -4-COO--                                                              H           1  Br   MDC    138.0--139.5                                                                           76                              CH.sub.3 -2-imidaz.                                                           H         H           S  EDIPA                                            30AS                                                                              1-Me.sub.2 NCOCH.sub.2 -                                                                H           1  Br   MDC    178.5-179.5                                                                            70                              5-tet.                                                                        H         H           S  EDIPA                                            30AT                                                                              1-C.sub.6 H.sub.5 -5-tet.                                                               C.sub.2 H.sub.5 O                                                                         1  Cl   DMF    139.5-140.5                                                                            62                              H         H           S  Na Salt                                          30AU                                                                              1-C.sub.6 H.sub.5 -5-tet.                                                               (CH.sub.3).sub.2 CHO                                                                      1  Cl   DMF    124.5-125.5                                                                            94                              H         H           S  Na Salt                                          30AV                                                                              1-Me.sub.2 NCOCH.sub.2 -                                                                C.sub.2 H.sub.5                                                                           1  Cl   MDC    146.5-148                                                                              80                              5-tet.                                                                        H         H           S  EDIPA                                            30AW                                                                              1-Me.sub.2 NCOCH.sub.2 -                                                                (CH.sub.3).sub.2 CH                                                                       1  Cl   MDC    180.0-181.5                                                                            73                              5-tet.                                                                        H         H           S  EDIPA                                            30AX                                                                              1-Me.sub.2 NCOCH.sub.2 -                                                                C.sub.2 H.sub.5 O                                                                         1  Cl   MDC    146.0-147.0                                                                            72                              5-tet.                                                                        H         H           S  TEA                                              30AY                                                                              1-C.sub.6 H.sub.5 -5-tet.                                                               CH.sub.3 O  1  Cl   DMF                                             H         6-CH.sub.3 O                                                                              S  Na Salt                                          30AZ                                                                              5-NH.sub.2 -2-(1,3,-                                                                    H           1  Br   EtOH   164.0-165.0                                                                            46                              4-thiadiaz.)                                                                  H         H           S  NaOMe       CH.sub.3 CN                          30BA                                                                              1-oxo-6-phen-                                                                           (CH.sub.3).sub.2 CH                                                                       1  Cl   DMF    224.0-226.0                                                                            51                              alenyl                                                                        H         H           O  Tl Salt     EtOAc                                30BB                                                                              2,6-Cl.sub.2 C.sub.6 H.sub.4                                                            H           1  Br   DMF    175.0-177.0                                                                            70                              H         H           O  Tl Salt                                          30BC                                                                              1-C.sub.6 H.sub.5 -5-tet.                                                               C.sub.6 H.sub.5                                                                           1  Cl   DMF    170.0-172.0                                                                            87                              H         H           S  Na Salt                                          30BD                                                                              6-NO.sub.2 -2-                                                                          H           1  Br   MEK    185-186                                  benzthiaz.                                                                    H         H           S  Tl Salt     CH.sub.3 CN                          30BE                                                                              6-NO.sub.2 -2-                                                                          H           1  Br   DMF    161-163  28                              benzoxaz.                                                                     H         H           S  Tl Salt     CH.sub.3 CN                          30BF                                                                              2-phthalimidyl                                                                          H           0  Br   DMF             33                              H         H           -- K Salt      EtOH--CH.sub.3 CN                    30BG                                                                              1-(4-Mor.CH.sub.2 --                                                                    H           1  Br   MDC    110-113  74                              CH.sub.2)-5-tet.                                                              H         H           S  TEA         EtOH                                 30BH                                                                              4-C.sub.6 H.sub.5 -5-oxo-                                                               H           0  Br   MEK    153-155  74                              1-tet.                                                                        H         H           -- K.sub.2 CO.sub.3                                                                          EtOH                                 30BI                                                                              1-(4-Mor.CH.sub.2 --                                                                    (CH.sub.2).sub.2 CH                                                                       1  Cl   MDC             85                              CH.sub.2)-5-tet.                                                              H         H           S  TEA                                              30BJ                                                                              2-pyrimidinyl                                                                           H           1  Br   MEK    170-72   40                              H         H           S  K.sub.2 CO.sub.3                                                                          EtOH--CH.sub.3 CN                    30BK                                                                              1-C.sub.6 H.sub.5 -5-tet.                                                               C.sub.2 H.sub.5                                                                           1  Cl   DMF    162-164  74                              H         5,6-(CH.sub.3 O).sub.2                                                                    S  Na Salt     EtOH--H.sub.2 O                      __________________________________________________________________________

EXAMPLE 31A-31C

Following a procedure similar to that described above in Example 17,substituting for the saccharin and the methyl2-chloro-2-phenylthioacetate used therein molar equivalent amounts of arespective appropriate 4-R₃ -R₄ -substituted saccharin and anappropriate Cl--CHR₂ --S--R₁ moiety, the following compounds of formula1, shown in TABLE C, were similarly prepared where in each instance, nis 1 and L is --S--. In each case, the thallium salt of the saccharinderivative was used, and the reactions were carried out in DMF.

                  TABLE C                                                         ______________________________________                                        Ex.   R.sub.1 /R.sub.2                                                                         R.sub.3 /R.sub.4                                                                        mp/From   Yield                                    ______________________________________                                        31A   C.sub.6 H.sub.5                                                                          H         144-146   51                                             COOMe      H         EtOH                                               31B   1-C.sub.6 H.sub.5 -5-tet.                                                                H         130-132   44                                             C.sub.6 H.sub.5 S                                                                        H         EtOH                                               31C   1-C.sub.6 H.sub.5 -5-tet.                                                                H         177-179   43                                             H          6-NO.sub.2                                                                              EtOH/CH.sub.3 CN                                   ______________________________________                                    

EXAMPLE 32A

A solution of 0.28 g (0.00067 mol) of2-(2,6-dichlorophenylthiomethyl)saccharin in 5 ml of MDC was treatedwith about 0.3 g (0.0017 mol) of 3-chloroperbenzoic acid with stirring,and the mixture was stirred for about 16 hours and quenched with aqueous10% sodium bisulfite solution. The reaction mixture was diluted withMDC, the layers separated and the organic layer washed sequentially withwater, saturated sodium bicarbonate, and saturated ammonium chloride,dried over sodium sulfate and evaporated to dryness in vacuo and theresidue chromatographed on silica gel with 10:1 MDC:diethyl ether. Therewas thus obtained 0.1 g (10%) of2-(2,6-dichlorophenylsulfonylmethyl)saccharin, mp 201.0°-203.0° C.

EXAMPLE 32B

Following a procedure similar to that described in Example 32A, 0.75 g(0.0023 mol) of 2-(2-pyrimidinylsulfinylmethyl) saccharin was oxidizedwith 0.4 g (0.0023 mol) of 3-chloroperbenzoic acid in 50 ml of MDC andthe product recrystallized from 75:25 acetonitrile:ethanol to give2-(2-pyrimidinylsuylfonylmethyl) saccharin, mp 225°-227° C.

EXAMPLE 33A

To a solution of 0.345 g (0.001 mol) of2-(5-mercapto-1,3,4-thiadiazol-2-ylthiomethyl)saccharin and 0.46 ml(0.003 mol) of triethylamine in 2 ml of DMF was added 0.37 g (0.002 mol)of 4-(2-chloroethyl)morpholine hydrochloride. The reaction mixture wasstirred at ambient temperature for about 24 hours, quenched by pouringinto water and extracted with ethyl acetate. The organic layer waswashed with water, then with brine and taken to dryness to give a yellowoil which was taken into chloroform and chromatographed on silica gel,eluting with ethyl acetate. There was thus obtained 0.225 g (49%) of2-(5-[2-(4-morpholinyl)ethylthio]-1,3,4-thiadiazol-2-ylthiomethyl)saccharin,mp 129°-131° C.

EXAMPLE 33B

Following a procedure similar to that described in Example 33A above,1.72 g (0.005 mol) of2-(5-mercapto-1,3,4-thiadiazol-2-ylthiomethyl)saccharin was reacted with1.44 g (0.01 mol) of 2-dimethylaminoethyl chloride hydrochloride in 10ml of DMF in the presence of 1.72 g (0.017 mol) of triethylamine to give1.2 g (58%) of 2-(5-[2-(N,N-dimethylamino)-ethylthio]-1,3,4-thiadiazol-2-ylthiomethyl))saccharin, mp 90.5°-91.5° C. (from ethylacetate).

EXAMPLE 33C

Following a procedure similar to that described above in Example 33A,0.69 g (0.002 mol) of2-(5-mercapto-1,3,4-thiadiazol-2-ylthiomethyl)saccharin was reacted with0.74 g (0.004 mol) of 1-(2-chloroethyl)piperidine hydrochloride in 4 mlof DMF in the presence of 0.4 g of triethylamine to give 0.55 g (60%) of2-(5-[2-(1-piperidinyl)ethylthio]-1,3,4-thiadiazol-2-ylthiomethyl)saccharin,mp 100.0°-101.0° C. (from ethyl acetate).

EXAMPLE 33D

Following a procedure similar to that described in Example 33A,2-(5-mercapto-1,3,4-thiadiazol-2-ylthiomethyl)saccharin is reacted with2-chloroethyldiethylamine hydrochloride in DMF in the presence oftriethylamine to give2-(5-[2-(diethylamino)ethylthio]-1,3,4-thiadiazol-2-ylthiomethyl)saccharin,mp 93.0°-94.5° C. (from cyclohexane:ethyl acetate).

EXAMPLE 33E

Following a procedure similar to that described in Example 33A, 1.72 g(0.005 mol) of 2-(5-mercapto-1,3,4 -thiadiazol-2-ylthiomethyl)saccharinwas reacted with 1.84 g (0.01 mol) of 1-(2-chloroethyl)piperidinehydrochloride in 10 ml of DMF in the presence of 2.4 ml of triethylamineto give 1.08 g (47%) of2-(5-[2-(piperidinyl)ethylthio]-2-thioxo-1,3,4-thiadiazolin-3-ylmethyl)saccharin,mp 89.0°-92.0° C., in which the 1,3,4-thiadiazol-2-ylthiomethyl groupunderwent rearrangement during the reaction.

EXAMPLE 34

To a solution of 0.44 g (0.0013 mol) of2-[1-(2-hydroxyethyl)-1H-tetrazol-5-ylthiomethyl]saccharin in 10 ml ofacetone was added chromic acid prepared from dilute sulfuric acid andsodium dichromate dihydrate (Jones' reagent) while maintaining thereaction mixture at 0° C. until a persistent orange-brown color remainedin the solution. The mixture was stirred for 1 hour at 0° C., then atambient temperature for about 6 hours, diluted with water and extractedwith ethyl acetate. The combined organic extracts were washed withwater, then with brine, dried and evaporated to dryness, and the residuechromatographed on silica gel, eluting with 5-15% methanol-MDC, to give0.29 g (63%) of2-[1-(2-carboxymethyl)-1H-tetrazol-5-ylthiomethyl]saccharin, mp 173°-75°C.

EXAMPLE 35

A solution of 1 g (0.0026 mol) of2-[1-(3-aminophenyl)-1H-tetrazol-5-ylthiomethyl]saccharin and 0.26 g(0.0026 mol) of succinic anhydride in 50 ml of dioxane was stirred atambient temperature for two hours, heated under reflux for six hours,stirred at ambient temperature for two days, then heated to reflux againand additional small amounts of succinic anhydride added over a periodof a few hours until TLC analysis indicated the absence of startingmaterial in the reaction mixture. The reaction was cooled, poured intodilute hydrochloric acid and ice water, and the solid which separatedwas collected, dried and recrystallized from 50:50 ethanol: acetonitrileto give 0.5 g (39%) of2-[1-(3-succinoylaminophenyl)-1H-tetrazol-5-ylthiomethyl]saccharin, mp197°-199° C.

EXAMPLE 36

5-Nitro-2-(1-phenyl-1H-tetrazol-5-ylthiomethyl)saccharin (1 g, 0.0024mol) was reduced over 3 spatulas of Rainey nickel (washed with THF priorto use) in 150 ml of THF under 50 psi hydrogen pressure. When reductionwas complete (in about 5 hours) the reaction mixture was filtered, thefilter pad washed with THF, and the filtrate evaporated to dryness togive a pale yellow, cloudy oil which was taken into hot ethanol andfiltered. On cooling, the product separated and was collected to give0.4 g (43%) of 5-amino-2-(1-phenyl-1H-tetrazol-5-ylthiomethyl)saccharinas yellow crystals.

EXAMPLE 37

A suspension of 0.4 g of5-amino-2-(1-phenyl-1H-tetrazol-5-ylthiomethyl)saccharin in 25 ml ofacetonitrile was treated with 0.08 g (0.001 mol) of acetyl chloride, themixture was heated under reflux for 30 minutes, treated with anadditional drop of acetyl chloride and refluxing continued for another30 minutes. Evaporation of the mixture to dryness afforded a white foamwhich was chromatographed on silica gel with 95:5 MDC:ethyl acetate togive 200 mg (43%) of5-acetylamino-2-(1-phenyl-1H-tetrazol-5-ylthiomethyl)saccharin.

EXAMPLE 38

A solution of 5 g (0.025 mol) of the sodium salt of1-phenyl-5-mercaptotetrazole in 50 ml of methyl ethyl ketone was addeddropwise with stirring to a warm solution of 3-chloro-1-iodopropane in300 ml of MEK. The mixture was stirred at 40° C. for six hours, allowedto stand at ambient temperature for about two days and the reactionmixture taken to dryness in vacuo. The residue was dissolved in MDC, thesolution washed with water and the aqueous washings back-extracted withMDC. The combined organic extracts were dried and taken to dryness togive a yellow oil which was chromatographed on silica gel, eluting withMDC. There was thus obtained 3.6 g (57%) of1-phenyl-5-(3-chloropropylthio)-1H-tetrazole as a pale yellow oil. (Inanother run, the same material was obtained as a white crystallinesolid, mp 33°-34° C.)

The product (3.5 g, 0.014 mol) was dissolved in 100 ml of MEK, 1.7 g(0.014 mol) of the sodium salt of thiophenol was added, the mixturewarmed at 40° C. for three hours, poured into potassium bicarbonatesolution and the mixture extracted with MDC. The combined organicextracts, on drying and evaporation to dryness, afforded a pale yellowoil which was chromatographed on silica gel with MDC to give 3.85 g(86%) of 1-phenyl-5-[3-(phenylthio)propylthio]-1H-tetrazole. (In anotherrun this same material was obtained as white crystals, mp 57°-59° C.)

A solution of 3.8 g (0.012 mol) of the product in 100 ml of carbontetrachloride was treated with 1.5 g (0.012 mol) of N-chlorosuccinimide,the mixture allowed to stand at ambient temperature for one hour, thenfiltered and the filtrate evaporated to dryness to give 4.3 g of1-phenyl-5-[3-chloro-3-(phenylthio)propylthio]-1H-tetrazole.

The product (0.012 mol) and 4.58 g (0.12 mol) of the thallium salt ofsaccharin dissolved in 75 ml of DMF was heated at 50° C. for threehours, allowed to stand at ambient temperature for two hours, filteredand the filter pad washed with DMF. The combined filtrate was pouredinto water, the mixture extracted with MDC, and the combined organicextracts were washed with brine and concentrated to dryness to give apale yellow oil which was chromatographed on silica gel with MDC to give2.45 g (41%) of2-[1-phenylthio-3-(1-phenyl-1H-tetrazol-5-ylthio)propyl]saccharin.

The product (1 g, 0.002 mol) was dissolved in MDC and oxidized with 0.34g (0.002 mol) of 3-chloroperbenzoic acid according to the proceduredescribed in Example 32A above. There was thus obtained 0.8 g (76%) of2-[1-phenylsulfinyl-3-(1phenyl-1H-tetrazol-5-ylthio)propyl]saccharin.

The product (1.6 g, 0.003 mol) was heated in 130 ml of diethylene glycoldimethyl ether at 120° C. for 45 minutes and the mixture cooled andpoured into water. The solid which separated was collected, dried anddissolved in MDC and the solution chromatographed on silica gel in MDC.There was thus obtained 1.2 g oftrans-2-[3-(1-phenyl-1H-tetrazol-5-ylthio)-1-propenyl]saccharin, mp191°-193° C.

EXAMPLE 39

Other 2-unsubstituted saccharins of formula II useful as intermediatesfor the preparation of the compounds of formula I can be prepared asfollows.

Reaction of 3-trifluoromethylbenzoic acid with thionyl chloride affords3-trifluoromethylbenzoyl chloride, which, on reaction with diethylamine,affords 3-trifluoromethyl-N,N-diethylbenzamide. Following a proceduresimilar to that described in Example 22A, reaction of the latter withs-butyl lithium and reaction of the resulting lithium salt with sulfurdioxide followed by sodium hydroxylaminesulfonate affords3-trifluoromethyl-2-aminosulfonyl-N,N-diethylbenzamide, which, onheating in glacial acetic acid, affords 7-trifluoromethyl saccharin.

Similarly, reaction of 4-cyclohexylbenzoic acid with thionyl chlorideaffords 4-cyclohexylbenzoyl chloride, which, on reaction withdiethylamine, affords 4-cyclohexyl-N,N-diethylbenzamide. Following aprocedure similar to that described in Example 22A, reaction of thelatter with s-butyl lithium and reaction of the resulting lithium saltwith sulfur dioxide followed by sodium hydroxylaminesulfonate affords4-cyclohexyl-2-aminosulfonyl-N,N-diethylbenzamide, which, on heating inglacial acetic acid, affords 6-cyclohexyl-saccharin.

Reaction of 6-aminosaccharin with methanesulfonyl chloride ortrifluoromethylsulfonyl chloride in MDC in the presence of pyridineaffords, respectively, 6-methylsulfonylaminosaccharin or6-trifluoromethylsulfonylaminosaccharin.

Diazotization of 6-aminosaccharin with nitrous acid in an acid mediumand decomposition of the resulting diazonium salt in the presence ofcupric cyanide or cupric chloride and sulfur dioxide, or cupric chlorideand an alkali metal salt of methyl mercaptan or trifluoromethylmercaptan affords, respectively, 6-cyanosaccharin,6-chlorosulfonylsaccharin, 6-methylthiosaccharin or6-trifluoromethylthiosaccharin. Reaction of the6-chlorosulfonylsaccharin in situ with ammonia or methanesulfonylamideaffords, respectively, 6-aminosulfonylsaccharin and6-methanesulfonylaminosulfonylsaccharin. Oxidation of6-methylthiosaccharin and 6-trifluoromethylthiosaccharin with two molarequivalents of 3-chloroperbenzoic acid affords 6-methylsulfonylsaccharinand 6-trifluoromethylsulfonylsaccharin, respectively.

Hydrolysis of 6-cyanosaccharin by heating with aqueous sodium hydroxideaffords saccharin-6-carboxylic acid. Reaction of 6-cyanosaccharin byheating with a catalytic amount of sulfuric acid in ethanol solutionaffords ethyl saccharin-6-carboxylate, which, on reduction with lithiumborohydride, affords 6-hydroxymethylsaccharin. Oxidation of the latterwith pyridine:chromium trioxide (2:1) complex (Collins reagent) in MDCaffords 6-formylsaccharin, which, on reductive amination with ammoniaand sodium cyanoborohydride, affords 6-aminomethylsaccharin.

Reaction of each of the 2-unsubstituted saccharins so-prepared withchloromethyl phenyl sulfide in the presence of potassium t-butoxide andtetrabutylammonium bromide, and reaction of the resulting2-phenylthiomethylsaccharins with sulfuryl chloride in MDC affords theR₄ -2-unsubstituted saccharins of formula I listed in TABLE D where, ineach instance, m and n are 0, R₁ is Cl and R₂ and R₃ are both hydrogen.

                  TABLE D                                                         ______________________________________                                        Example           R.sub.4                                                     ______________________________________                                        39A               7-CF.sub.3                                                  39B               6-cyclohexyl                                                39C               6-CH.sub.3 SO.sub.2 NH                                      39D               6-CF.sub.3 SO.sub.2 NH                                      39E               6-CN                                                        39F               6-NH.sub.2 SO.sub.2                                         39G               6-CH.sub.3 SO.sub.2 NHSO.sub.2                              39H               6-CH.sub.3 SO.sub.2                                         39I               6-CF.sub.3 SO.sub.2                                         39J               6-HOOC                                                      39K               6-HOCH.sub.2                                                39L               6-OHC                                                       39M               6-NH.sub.2 CH.sub.2                                         ______________________________________                                    

EXAMPLE 40

Following a procedure similar to that described in Example 4 above,substituting for the 2-chloromethyl-4-chlorosacchar in and the sodium1-phenyltetrazole salt used therein molar equivalent amounts of arespective appropriate 2-chloromethyl-R₄ -saccharin described in TABLE Dabove and an appropriate L_(n) R₁ moiety, the following compounds listedin TABLE E, where R₃ in each instance, unless noted otherwise, ishydrogen, are prepared.

                  TABLE E                                                         ______________________________________                                        Example                                                                              n     L     R.sub.1        R.sub.4                                     ______________________________________                                        40A    1     S     1-C.sub.6 H.sub.5 -5-tet.                                                                    7-CF.sub.3                                  40B    1     S     1-C.sub.6 H.sub.5 -2-(1,3,4-triaz.)                                                          6-cyclohexyl                                40C    1     S     1-(4-Mor.CH.sub.2 CH.sub.2)-5-tet.                                                           6-CH.sub.3 SO.sub.2 NH                      40D    1     S     3-(pyridyl)-5-tet.                                                                           6-CF.sub.3 SO.sub.2 NH                      40E    0     --    4-(3-pyridyl)-5-thioxo-1-tet.                                                                6-CN                                        40F    0     --    2-Me-5-thioxo-1-tet.                                                                         6-NH.sub.2 SO.sub.2                         40G    1     S     2-Me-5-tet.    6-CH.sub.3 SO.sub.2 NHSO.sub.2              40H    1     S     5-Me-2-(1,3,4-thiadiaz.)                                                                     6-CH.sub.3 SO.sub.2                         40I    1     S     1-Me-2-(1,3,4-triaz.)                                                                        6-CF.sub.3 SO.sub.2                         40J    1     S     4-C.sub.6 H.sub.5 -2-(1,3,5-thiadiaz.)                                                       6-HOOC                                      40K    1     S     5-HS-2-(1,3,4-thiadiaz.)                                                                     6-HOCH.sub.2                                40L    0     1     4-C.sub.6 H.sub.5 -5-thioxo-1-tet.                                                           6-OHC                                       40M    1     S     5-CH.sub.3 -2-(1,3,4-thiadiaz.)                                                              6-NH.sub.2 CH.sub.2                         40N    1     S     1-C.sub.6 H.sub.5 -5-tet                                                                     5-CH.sub.3 O(a)                             ______________________________________                                         (a) R.sub.3 is isopropyl. Prepared by reaction of N,Ndiethyl-carbamyl         chloride with the lithium salt of 2bromo-5-methoxy-isopropylbenzene;          reaction of the resuluting (79%) N,Ndiethyl-2-isopropyl-4-methoxybenzamid     with sbutyl lithium followed by sulfur dioxide and sodium hydroxylamine       sulfonate; heating the resulting (56%)                                        N,Ndiethyl-2-aminosulfonyl-4-methoxy-6-isopropylbenzamide in glacial          acetic acid; reaction of the resulting (100%) diethylammonium salt of         4isopropyl- 6methoxysaccharin with chloromethyl phenyl sulfide; reaction      of the resulting (88%) 2phenylthiomethyl-4-isopropyl-6-methoxy saccharin      with sulfuryl chloride, and reaction of the resulting (88%)                   2chloromethyl-4-isopropyl-6-methoxysaccharin with the sodium salt of          1phenyl-5-mercaptotetrazole.                                             

BIOLOGICAL TEST RESULTS

Measurement of the inhibition constant, K_(i), of a HLE-inhibitorcomplex has been described for "truly reversible inhibition constants"usually concerning competitive inhibitors. [Cha, Biochem. Pharmacol.,24, 2177-2185 (1975)]. The compounds of the present invention, however,do not form truly reversible inhibitor complexes but are consumed by theenzyme to some extent. Thus, instead of measuring a K_(i), a K_(i) * iscalculated which is defined as the ratio of the k_(off) /k_(on), therate of reactivation of the enzyme to the rate of inactivation of theenzyme. The values of k_(off) and k_(on) are measured and K_(i) * isthen calculated.

The rate of inactivation, k_(on), of enzymatic activity was determinedfor the compounds tested by measuring the enzyme activity of an aliquotof the respective enzyme as a function of time after addition of thetest compound. By plotting the log of the enzyme activity against time,an observed rate of inactivation, k_(obs), is obtained which can berepresented as k_(obs) =1n2/t_(1/2) where t_(1/2) is the time requiredfor the enzyme activity to drop by 50%. The rate of inactivation is thenequal to ##EQU1## where [I] is the concentration of the inhibitingcompound.

The reactivation constant, k_(off), is similarly determined and theinhibition constant, K_(i), * is then calculated as

    K.sub.i *=k.sub.off /k.sub.on

The values obtained for k_(on) and K_(i) * for specific substitutedsaccharin derivatives are shown in TABLE F, the compounds beingidentified by the Example numbers above where their preparations aredescribed.

                  TABLE F                                                         ______________________________________                                        Elastase             α-Chymotrypsin                                            10.sup.-3 × k.sub.on                                                               K.sub.i *  10.sup.-3 × k.sub.on                                                             K.sub.i *                               Example                                                                              (M.sup.-1 sec.sup.-1)                                                                    (nM)       (M.sup.-1 sec.sup.-1)                                                                  (nM)                                    ______________________________________                                         1     0.63       102        1.2      917                                      2     4.9        45         2.9       51                                      3     450        0.5        5.8       26                                      4     20          12                                                          5     44         6          6.0       25                                      7     5.2        15                                                           8     1.0        81         2.1      523                                      9     2.5        32                                                          10     7.0        11         7.0      157                                     11     4.6                                                                    12     0.97       82         1.1      1000                                    13     0.3        285        2.6      423                                     14     0.6        138        2.8      392                                     15     3.2        69                                                          16                2,600                                                       17     2.9        270                                                         18     1.0        100        0.21     620                                     19                8,500                                                       21     950        0.5                                                         22A    12.4       6.0                                                         22B    2.4        90                                                          22C    105        0.4                                                         22D    75.8       1.3                                                         22E    4.7        91                                                          22F    20         6.5                                                         22G    3.0        50                                                          22H    25         1.2                                                         23A    30         9                                                           23B    50         4.4                                                         27     7.5        13                                                          28     50.7       2.5                                                         29     1.1        120                                                         30A               10,500                                                      30C    2.5        17                                                          30D    0.8        85                                                          30E    7.3        12.7                                                        30F               >>85,000                                                    30G    9.3        7.7                                                         30H    3.2                                                                    30I    0.45       650                                                         30J    14.0       10                                                          30L    6.5        7.6                                                         30M    1.0        10                                                          30N    0.25       220                                                         30-O   0.03       2,000                                                       30Q    1.38       70.4                                                        30R    2.3        36                                                          30S    1.81       40.4                                                        30T    1.1        14.5                                                        30U    5.6        13.6                                                        30V    24         15                                                          30W    1.5        80                                                          30X    0.55       143                                                         30Z    70         0.5                                                         30AB   2.8        23                                                          20AC   0.19       246                                                         30AD   7.0        11.6                                                        30AE   63.2       2.0                                                         30AF   4.2        12.5                                                        30AG              >1,000                                                      30AH   1.1        60                                                          30AI   53.8       2                                                           30AJ   1.8        15.5                                                        30AK   94         0.3                                                         30AL   100        0.7                                                         30AM   12.3       4.5                                                         30AN   19         30                                                          30AP   1.3        51                                                          30AQ   0.9        260                                                         30AR   0.3        153                                                         30AS   1.7        40                                                          30AT   45.3       3                                                           30AU   8.9        17.5                                                        30AV   7.6        15                                                          30AW   30         1                                                           30AX   7.5        16                                                          30AY   49         0.6                                                         30BA   42         0.8                                                         30BB              >500                                                        30BC   5.8        80                                                          30BD   11.7       8                                                           30BE   7.4        250                                                         30BF   0.02       40,000                                                      30BG   1.7        50                                                          30BH              >10,000                                                     30BI   39         0.5                                                         31C    3.4        300                                                         32A    0.6        145                                                         33     3.6        12                                                          33B    4.0        18                                                          33C    0.2        350                                                         34     0.4        256                                                         35     3.6        22                                                          37                >90,000                                                     38     43         2                                                           ______________________________________                                    

In the compound of formula I as described at pages 9-11 above R₁ is inaddition to those moieties described at pages 9-10 above:

phenyl substituted by 1-(4-lower-alkylpiperazin-1-yl) carbonyl,4-morpholinylsulfonyl, formyl, lower-alkoxycarbonyl,4-thiamorpholinylsulfonyl or the S-dioxide thereof, hydroxy-lower-alkyl,halo-lower-alkyl, 4-morpholinyl-lower-alkylaminocarbonyl,4-morpholinyl-lower-alkoxycarbonyl,1-(4-lower-alkylpiperazin-1-yl)sulfonyl, 4-morpholinyl-lower-alkoxy,di-lower-alkylamino-lower-alkylaminosulfonyl or an N-lower-alkylderivative thereof, halomethyl, lower-alkyl-sulfonyl, phenyl,4,5-dihydrooxazol-2-yl, lower-alkyltetrazol-5-yl, 4-morpholinylcarbonyl,nitrophenylazo, carboxyl or di-lower-alkylphosphonyl,

or heterocyclyl selected from pyridazin-3-yl, 4-pyron-3-yl,quinolin-8-yl, 1,3,4-oxadiazol-2-yl, coumarin-7-yl, saccharin-6-yl,imidazol-2-yl, 1,3,4-triazol-2-yl, thiazol-2-yl,2-thioxo-2,3-dihydro-1,3,4-oxadiazol-3-yl, 1,2,5-thiadiazol-3-yl,2-thioxo-2,3-dihydro-1,3,4-thiadiazol-3-yl,2-thioxo-2,3-dihydro-1,3,4-thiadiazol-5-yl, 1,2,3-triazol-2-yl,1,2,4-triazin-5-yl, 5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-yl,isoxazol-5-yl, isoxazol-3-yl, 5-oxo-1,2,4-oxadiazol-4-yl, pyridyl,1,1,3-trioxo-tetrahydro-1,2,5-thiadiazol-2-yl,6,7-dihydro-1H-1,2,4-triazolo [3,4-b] [1,3]thiazin-3-yl,4,5-dihydro-5-oxo-1,2,4-oxadiazol-4-yl, 2,5-dioxopyrrolidin-1-yl,3-indolyl, oxazol-2-yl, thiazol-4-yl,2,3-dihydro-2-oxo-5-phenyl-1,3,4-thiadiazol-3-yl and2,3-dihydro-2-oxo-5-phenyl-1,3,4-oxadiazol-3-yl,

or heterocyclyl as defined at page 9 or 93 above substituted on anyavailable nitrogen atom by phenyl substituted bycarboxy-lower-alkanoylamino,

or heterocyclyl as defined at page 9 or 93 above substituted on anyavailable carbon atom by di-lower-alkylamino-lower-alkyl,4-morpholinyl-lower-alkylamino, cyano, 1-piperidinyl-lower-alkyl,hydroxy-lower-alkyl, phenylsulfonyl, toluenesulfonyl, halo,tri-lower-alkylsilyl, carboxy or alkali metal salt thereof, furyl,trifluoromethyl, 2-benzothiazolyl, lower-alkylsulfonyl, aminocarbonyl,benzyl, 4-morpholinyl, pyridinyl, lower-alkoxy, pyrazinyl,lower-alkoxycarbonyl-lower-alkyl, di-lower-alkylaminosulfonyl,4-morpholinylcarbonyl, lower alkanoyl, benzyloxy, hydroxy, phenylsubstituted by trifluoromethyl, lower-alkoxy-poly-lower-alkoxy,methylenedioxy or lower alkoxycarbonyl or benzoyl or benzoyl substitutedby lower-alkoxy or halo,

or, when L is --O-- and n is 1, cycloheptatrienon-2-yl or, when L is--S-- and n is 1, cyano or lower-alkoxythiocarbonyl or, when L is --SO₂-- and n is 1, lower-alkyl or trifluoromethyl; and

In the compound of formula I as described at pages 9-11 above R₃ is alsodi-lower-alkylamino and R₄ is hydrogen or from one to three substituentsselected from those substituents described at pages 10-11 above and fromcarboxy-lower-alkoxy, lower-alkoxycarbonyl-lower-alkoxy anddi-lower-alkylaminocarbonyloxy.

A compound of formula I wherein n is 0 and R₁ is 1,2,3-triazol-1-yl isprepared by condensation of the corresponding compound of formula Iwherein R₁ is halo with an alkali metal azide and then cycloaddition ofthe resulting azide with the corresponding substituted or unsubstitutedacetylene. The preferred alkali metal azide is sodium azide. Thecondensation is carried out with or without heating or cooling,preferably at room temperature, in an inert solvent, for examplebenzene, toluene or dimethylformamide, optionally using a crown ether,for example 18-crown-6 ether. The cycloaddition is preferably carriedout in the same inert solvent with heating.

In addition to those particularly preferred compounds of formula Idescribed at lines 8-15 of page 14 above also particularly preferred arecompounds of formula I wherein m is 0, R₂ is hydrogen, R₃ is hydrogen,halo, primary or secondary lower-alkyl or lower-alkoxy, R₄ is hydrogen,hydroxy, lower-alkoxy, lower-alkoxy-lower-alkoxy,lower-alkoxy-poly-lower-alkyleneoxy, carboxy-lower-alkoxy orlower-alkoxycarbonyl-lower-alkoxy and:

n is 1, L is --O-- and R₁ is phenyl substituted by halo,1-(4-lower-alkylpiperazin-1-yl)carbonyl, 4-morpholinylsulfonyl,4-thiamorpholinylsulfonyl or the S-dioxide thereof,4-morpholinyl-lower-alkylaminocarbonyl,4-morpholinyl-lower-alkoxycarbonyl, 1-(4-lower-alkylpiperazin-1-yl)sulfonyl, di-lower-alkylamino-lower-alkylaminosulfonyl and/or4-morpholinylcarbonyl or 1,2,5-thiadiazol-3-yl or 1,2,5-thiadiazol-3-ylsubstituted by 4-morpholinyl or isoxazolyl substituted bylower-alkoxycarbonyl; or

n is 1, L is --S-- and R₁ is 1,3,4-oxadiazol-2-yl substituted on anyavailable carbon atom by furyl, benzyl, pyridinyl, pyrazinyl or phenyl;or

n is 0 and R₁ is 1,2,3-triazol-1-yl or 1,2,3-triazol-2-yl substituted onany available carbon atom by cyano or lower-alkylsulfonyl.

EXAMPLES 41A-L

Further examples of compounds of formula I wherein m is 0 and R₂, R₃ andR₄ are each hydrogen were prepared from 2-(chloromethyl)saccharin (or,if noted, 2-(bromomethyl)saccharin) and in each example thecorresponding R₁ -L_(n) -H except as noted and are described in TABLE G.

                                      TABLE G                                     __________________________________________________________________________                          M.p. (°C.)                                                                     Yield (%)                                       Example                                                                            R.sub.1 -L.sub.n From    Method                                          __________________________________________________________________________    41A  {5-[2-(1-piperidinyl)ethylthio]-                                                               100-101 60                                                   1,3,4-thiadiazol-2-yl}thio                                                                     EtOAc   A                                               41B  {5-[2-(diethylamino)ethyl]-1,3,4,-                                                             93-94.5 44                                                   thiadiazol-2-yl}thio                                                                           C.sub.6 H.sub.12 /EtOAc                                                               B                                               41C  {5-[2-(4-morpholinyl)ethylamino]-                                                              159-161 57                                                   1,3,4-thiadiazol-2-yl}thio                                                                     EtOAc   B                                               41D  4,5-dicyanoimidazol-1-yl                                                                       143-14  50                                                                    CHCl.sub.3                                                                            D                                               41E  trifluoromethylsulfonyl                                                                        134-137 25                                                                            E                                               41F  2-formyl-4-nitrophenoxy                                                                        168-171 I or J                                                                EtOH/MeCN                                               41G  2-hydroxymethyl-4-nitrophenoxy                                                                 150-152 92                                                                            G                                               41H  2-chloromethyl-4-nitrophenoxy                                                                  148-(slow)                                                                              30.6                                                                        H                                               41I  (5,7-dichloroquinolin-8-yl)oxy                                                                 220.5-222.5                                                                           46                                                                    EtOH/MeCN                                                                             I                                               41J  4-chloromethyl-2-nitrophenoxy                                                                  131-133 32                                                                    EtOH                                                    14K  4-(4-nitrophenylazo)phenoxy                                                                    217-219 63                                                                            J                                               41L  2,4-dichloro-3-(4-methyl-1-                                                                    >190*   32                                                   piperazinylcarbonyl)phenoxy                                                                    Et.sub.2 O                                                                            L                                               __________________________________________________________________________     A: By alkylation with 1(2-chloroethyl)piperidine in dimethylformamide at      room temperature of                                                           2[(5mercapto-1,3,4-thiadiazol-2-yl)thiomethyl]saccharin, prepared in turn     by condensation of 2(bromomethyl)saccharin and 1,3,4thiadiazol-2,5-dithio     with sodium methoxide in ethanol at reflux in 38% yield (m.p.                 204-206.5° C. from 1,2dichloroethane, 38% yield).                      B: From 2(bromomethyl)saccharin with ethanol as solvent and sodium            methoxide as base.                                                            D: From 2(bromomethyl)saccharin and tetrahydrofuran as solvent.               E: By oxidation of the corresponding sulfide.                                 G: By reduction of the compound of Example 41F.                               H: By displacement of hydroxy in the compound of Example 41G by chloro.       I: With acetonitrile as solvent and methyltriazabicyclodecene as base.        J: With dimethylformamide as solvent and thallium ethoxide as base.           L: With methyl ethyl ketone as solvent and potassium carbonate as base.       *Hydrochloride salt.                                                     

EXAMPLES 42A-BU

Further examples of compounds of formula I wherein m is 0 except Example42B wherein m is 1, R₂ and R₄ are each hydrogen and R₃ is isopropyl wereprepared from 2-chloromethyl-4-isopropylsaccharin (Example 22E above)(or, if noted, 2-bromomethyl-4-isopropylsaccharin) and in each examplethe corresponding R₁ -L_(n) -H except as noted and are described inTABLE H.

                                      TABLE H                                     __________________________________________________________________________                           M.p. (°C.)                                                                     Yield (%)                                      Example                                                                            R.sub.1 -L.sub.n  From    Method                                         __________________________________________________________________________    42A  (5-cyclohexylamino-1,3,4-                                                                       202-205 51                                                  thiadiazol-2-yl)thio                                                                            EtOH    A                                              42B  (2-phenyltetrazol-5-yl)thio                                                                     95-97   39.5                                                (m = 1)           EtOH    B                                              42C  methylsulfonyl    148.5-150.5                                                                           40.3                                                                  EtOH    C                                              42D  1,1,3-trioxotetrahydro-1,2,5-                                                                   Foam    53                                                  thiadiazol-2-yl           D                                              42E  (2-methyl-4-pyron-3-yl)oxy                                                                      136.5-138                                                                             48                                                                    EtOAc/C.sub.6 H.sub.6                                                                 E                                              42F  4-[(4-methylpiperazin-1-yl)-                                                                    160-165*                                                                              60                                                  carbonyl]phenoxy  Et.sub.2 O                                                                            F                                              42G  (6-hydroxymethyl-4-pyron-3-yl)oxy                                                               144-145 38                                                                    EtOAc/C.sub.6 H.sub.14                                                                A                                              42H  {6-[2-(4-morpholinyl)ethylthio]-                                                                53-93*  87                                                  1,3,4-thiadiazol-2-yl}thio                                                                      iPrOH/Et.sub.2 O                                                                      H                                              42I  2,4-dichloro-6-(4-morpholinyl-                                                                  153-155 53                                                  sulfonyl)phenoxy  EtOH    I                                              42J  2-chloro-4-(4-morpholinyl-                                                                      194-196 54                                                  sulfonyl)phenoxy  EtOH    J                                              42K  {5-[2-(1-piperidinyl)ethylthio]-                                                                oil     50%                                                 1,3,4-thiadiazol-2-yl}thio                                                                              K                                              42L  {5-[2-(diethylamino)ethyl]-1,3,4-                                                               oil     38                                                  thiadiazol-2-yl}thio                                                     42M  {5-[2-(dimethylamino)ethylthio]-                                                                124-125.5*                                                                            62                                                  1,3,4-thiadiazol-2-yl}thio                                                                      iPrOH   M                                              42N  {5-[2-(4-morpholinyl)ethyl]-                                                                    142-143*                                                                              71%                                                 1,3,4-thiadiazol-2-yl}thio                                                                      iPrOH   L                                              42O  {5-[2-(1-piperidinyl)ethyl]-                                                                    149-150*                                                                              61                                                  1,3,4-thiadiazol-2-yl}thio                                                                      EtOH    O                                              42P  (4,5-dichloropyridazin-3-yl)oxy                                                                 183-186 40                                                                    Et.sub.2 O                                                                            E                                              42Q  4,5-di(methoxycarbonyl)-1,2,3-                                                                  153-154 30                                                  triazin-1-yl      EtOAc/C.sub.6 H.sub.14                                                                Q                                              42R  2-methoxycarbonyl-5-methoxy-                                                                    104-105 30                                                  phenoxy                   J                                              42S  2-fluoro-4-(4-morpholinyl-                                                                      165-167 68.7                                                sulfonyl)phenoxy  EtOH    J                                              42T  2-chloro-4-(1,1-dioxo-4-thia-                                                                   Not sharp                                                                             29.6                                                morpholinylsulfonyl)phenoxy                                                                     EtOH    T                                              42U  5-phenylsulfonyl-1,2,3-triazol-                                                                 163.5-168                                                                             32                                                  1-yl              EtOAc   Q                                              42V  4-trimethylsilyl-5-phenylsulfonyl-                                                              200.5-201.5                                                                           22                                                  1,2,3-triazol-1-yl                                                                              EtOAc   Q                                              42W  4-methoxycarbonyl-1,2,3-triazol-                                                                192-193 66                                                  1-yl              EtOAc   Q                                              42X  (2-ethyl-4-pyron-3-yl)oxy                                                                       93-98   85                                                                            X                                              42Y  5-methoxycarbonyl-1,2,3-triazol-                                                                150.5-151.5                                                                           23                                                  1-yl              EtOAc   Q                                              42Z  4-ethoxycarbonyl-5-phenyl-1,2,3-                                                                177.5-179                                                                             37                                                  triazol-1-yl      EtOAc   Q                                              42AA 4-phenyl-5-ethoxycarbonyl-1,2,3-                                                                117-119 56                                                  triazol-1-yl      EtOAc/C.sub.6 H.sub.12                                                                Q                                              42AB 2,6-difluoro-4-(4-morpholinyl-                                                                  185-187 40                                                  sulfonyl)phenoxy  EtOH    J                                              42AC 4,6-difluoro-2-(4-morpholinyl-                                                                  176-178 38.6                                                sulfonyl)phenoxy  EtOH    J                                              42AD 4,5-difluoro-2-(4-morpholinyl-                                                                  140.5-142.5                                                                           58.6                                                sulfonyl)phenoxy  EtOH    J                                              42AE (3-phenylcoumarin-7-yl)oxy                                                                      145-147 63                                                                    EtOAc/C.sub.6 H.sub.12                                                                E                                              42AF (4-phenylcoumarin-7-yl)oxy                                                                      219-221 53                                                                    MeCN    E                                              42AG 4-fluoro-2-(4-morpholinyl-                                                                      169-171 27.4                                                sulfonyl)phenoxy  EtOH    J                                              42AH 2,5-difluoro-4-(4-morpholinyl-                                                                  158-160 44                                                  sulfonyl)phenoxy  EtOH    J                                              42AI 3-[2-(4-morpholinyl)ethylamino-                                                                 Foam*   10                                                  carbonyl]phenoxy          F                                              42AJ pentafluorophenoxy                                                                              90-92   10                                                                    C.sub.6 H.sub.14                                                                      F                                              42AK 2,4-dichloro-3-[2-(4-morpholinyl)-                                                              Foam*   30                                                  ethoxycarbonyl]phenoxy                                                   42AL (5-phenyl-1,3,4-oxadiazol-2-yl)-                                                                132-134.5                                                                             60                                                  thio              EtOH    AL                                             42AM 4-carboxy-1,2,3-triazol-1-yl                                                                    182.5-183.5                                                                           21                                                                    MeCN    Q                                              42AN 4-phenyl-5-(4-methylphenyl-                                                                     173-174.5                                                                             32                                                  sulfonyl)-1,2,3-triazol-1-yl                                                                    EtOAc   Q                                              42AO 4-(4-methylphenylsulfonyl)-5-                                                                   179-181.5                                                                             40                                                  phenyl-1,2,3-triazol-1-yl                                                                       EtOAc   Q                                              42AP (6-chloro-4-trifluoromethyl-                                                                    169-170 29                                                  coumarin-7-yl)oxy EtOH    X                                              42AQ (4-methylcoumarin-7-yl)oxy                                                                      178-179.5                                                                             18                                                                    iPrOH   E                                              42AR 3-[(4-methylpiperazin-1-yl)-                                                                    >150*   34                                                  sulfonyl]phenoxy  Et2O    F                                              42AS 3-[2-(4-morpholinyl)ethoxy]-                                                                    102-105*                                                                              35                                                  phenoxy           Et.sub.2 O                                                                            F                                              42AT 3-{2-[(dimethylamino)ethyl]methyl-                                                              115-118*                                                                              60                                                  aminosulfonyl}phenoxy                                                                           Et.sub.2 O                                                                            F                                              42AU [3-(benzothiazol-2-yl)coumarin-7-                                                               239-240 30                                                  yl]oxy            MeCN    E                                              42AV (saccharin-6-yl)oxy                                                                             90-110  11                                                                            AV                                             42AW 4-phenylsulfonyl-1,2,3-triazin-                                                                 219.5-220.5                                                                           87                                                  1-yl              EtOAc   Q                                              42AX ethoxythiocarbonylthio                                                                          oil     57                                                                            AX                                             42AY 2-fluoro-4-(4-morpholinyl-                                                                      149-151 83.7                                                sulfonyl)phenylthio                                                                             EtOH    J                                              42AZ 4-ethylsulfonyl-5-isopropyl-                                                                    137-139 20                                                  1,2,3-triazin-1-yl                                                                              EtOAc/C.sub.6 H.sub.12                                                                Q                                              42BA 4-isopropyl-5-ethylsulfonyl-                                                                    150-152 6-11                                                1,2,3-triazin-1-yl                                                                              EtOAc/C.sub.6 H.sub.12                                                                Q                                              42BB 2-fluoro-4-(4-morpholinyl-                                                                      198-201 42.5                                                sulfonyl)phenylsuflinyl   BB                                             42BC 2-fluoro-4-(4-morpholinyl-                                                                      219-221 87.5                                                sulfonyl)phenylsulfonyl                                                                         EtOH    BC                                             42BD 4,5-di(aminocarbonyl)-1,2,3-                                                                    261-262 68                                                  triazin-1-yl      MeCN    Q                                              42BE 4,5-dicarboxy-1,2,3-triazin-1-yl                                                                211-215 15                                                  (monosodium salt) THF     Q                                              42BF 4,5-dicarboxy-1,2,3-triazin-1-yl                                                                        Q, BF                                          42BG [4-(4-morpholinyl)-1,2,5-                                                                       132-134 50                                                  thiadiazol-3-yl]oxy                                                                             EtOH    J                                              42BH 4-methylsulfonylphenoxy                                                                         147-150 79                                                                            J                                              42BI [4-(ethoxycarbonylmethyl)thiazol-                                                               906-97  20                                                  2-yl]thio         CCl.sub.4 /C.sub.6 H.sub.12                                                           BI                                             42BJ 4-trimethylsilyl-5-dimethylamino-                                                               196-198 91                                                  sulfonyl-1,2,3-triazol-1-yl                                                                     MeCN    Q                                              42BK 4-(1,1,-dimethyl)ethyl-5-dimethyl-                                                              207-209 7                                                   aminosulfonyl-1,2,3-triazol-1-yl                                                                EtOAc/C.sub.6 H.sub.12                                                                Q                                              42BL 4-dimethylaminosulfonyl-5-(1,1-                                                                 201-202 3                                                   dimethyl)ethyl-1,2,3-triazol-1-yl                                                               EtOAc/C.sub.6 H.sub.12                                                                Q                                              42BM 4-trimethylsilyl-1,2,3-triazol-                                                                 oil     81                                                  1-yl                      Q                                              42BN 2,6-dichlorophenoxy                                                                             146-148 70                                                                    Et.sub.2 O/C.sub.6 H.sub.14                                                           F                                              42BO 2,4,6-trichlorophenoxy                                                                          140-142 28                                                                    t-BuOMe BO                                             42BP 2,4-dichloro-3-(4-methyl-1-                                                                     >175*   75                                                  piperazinylcarbonyl)phenoxy                                                                     Et.sub.2 O                                                                            F                                              42BQ 2,4-dichloro-3-carboxyphenoxy                                                                   194-196 57                                                                    C.sub.6 H.sub.14 /CH.sub.2 C.sub.12                                                   BQ                                             42BR 3-[2-(4-morpholinyl)ethoxy-                                                                     >115*   51                                                  carbonyl]phenoxy  Et.sub.2 O                                                                            F                                              42BS 2,4-dichloro-3-[2-(4-morpholinyl)-                                                              149-152*                                                                              30                                                  ethylaminocarbonyl]phenoxy                                                                      Et.sub.2 O                                                                            F                                              42BT 4-(4-morpholinylsulfonyl)phenoxy                                                                glass   BT                                             42BU 4-trimethylsilyl-5-methoxy-                                                                     122.5-123.5                                                                           68                                                  carbonyl-1,2,3-triazol-1-yl                                                                     EtOAc/C6H12                                                                           Q                                              __________________________________________________________________________     A: With dimethylformamide as solvent and triethylamine as base.               B: In three steps by, first, condensation of the thallium salt of             4isopropylsaccharin formed from 4isopropylsaccharin and thallium ethoxide     with 1phenyl-5-(3-chloro-3-phenylthiopropyl)tetrazole in dimethylformamid     in 77% yield, second, oxidation of the resulting                              2[3(1-phenyltetrazol-5-yl)-1-(phenylthio)propyl4-isopropylsaccharin with      mchloroperbenzoic acid in 87% yield and, third, thermal elimination of th     resulting 2[3(1-phenyltetrazol-5-yl)-1-(phenylthio)propyl                     4isopropylsaccharin in 59% yield.                                             C: In two steps, first, condensation of                                       2(chloromethyl)-4-isopropylsaccharin with sodium methylthiolate and,          second, oxidation of the resulting 2(methylthio)-4-isopropylsaccharin.        D: With toluene as solvent, 1,1,3trioxotetrahydro-1,2,5-thiadiazole and       tetrabutylammonium bromide.                                                   E: With dimethylformamide as solvent and sodium hydride as base.              F: With methyl ethyl ketone as solvent and potassium carbonate as base.       *Hydrochloride salt.                                                          H: In two steps, first, condensation of                                       2(chloromethyl)-4-isopropylsaccharin with 1,3,4thiadiazol-2,5-dithiol         monopotassium salt in methanol in 83% yield and, second, condensation of      the resulting                                                                 2[(5mercapto-1,3,4-thiadiazol-2-yl)thiomethyl4-isopropylsaccharin with        4(2-chloroethyl)morpholine hydrochloride in dimethylformamide as solvent      and triethylamine as base in 87% yield. *Hydrochloride salt.                  I: With dichloromethane as solvent and diazabicycloundecene as base.          J: With acetonitrile as solvent and methyltriazabicyclodecene as base.        K: By alkylation of                                                           2[(5mercapto-1,3,4-thiadiazol-2-yl)thiomethyl4-isopropylsaccharin (Exampl     42H) with 1(2-chloroethyl)piperidine hydrochloride in dimethylformamide a     solvent and triethylamine as base.                                            L: With ethanol as solvent and sodium methoxide as base.                      M: By alkylation of                                                           2[(5mercapto-1,3,4-thiadiazol-2-yl)thiomethyl4-isopropylsaccharin (Exampl     42H) with (2chloroethyl)dimethylamine hydrochloride in dimethylformamide      as solvent and triethylamine as base. *Maleate salt.                          N: With ethanol as solvent and sodium methoxide as base. *Maleate salt.       O: With ethanol as solvent and triethylamine as base. *Maleate salt.          Q: In two steps, first, condensation of                                       2(chloromethyl)-4-isopropylsaccharin with sodium azide and a catalytic        acmount of 18crown-6 ether in benzene or benzenetetrahydrofuran or            benzenedimethylformamide at room temperature and, second, cycloaddition o     the resulting 2(azidomethyl)-4-isopropylsaccharin with the corresponding      acetylene, in this example dimethyl aceylenedicarboxylate, in the same        solvent with or without heating.                                              T: In two steps, first, condensation of                                       2(chloromethyl)-4-isopropylsaccharin and                                      2chloro-4-(4-thiamorpholinyl)phenol with acetonitrile as solvent and          methyltriazabicyclodecene as base in 74.7% yield and, second, oxidation o     the resulting                                                                 2[2chloro-4-(4-thiamorpholinyl)phenoxymethyl4-isopropyl-saccharin with        mchloroperbenzoic acid in 38.5% yield.                                        X: With dimethylformamide as solvent and cesium carbonate as base.            AV: In two steps, first, condensation of                                      2(chloromethyl)-4-isopropylsaccharin and 2benzyl-6-hydroxysaccharin with      methyl ethyl ketone as solvent and potassium carbonate as base in 43%         yield and, second, debenzylation by catalytic hydrogenation over palladiu     on carbon in methanol containing ammonium formate in 26% yield.               BB: By oxidation of the compound of Example 42AY with one molar equivalen     of mchloroperbenzoic acid.                                                    BC: By oxidation of the compound of Example 42BB with one molar equivalen     of mchloroperbenzoic acid.                                                    BF: Obtained impure.                                                          BI: With acetonitrile as solvent and sodium hydride as base.                  BO: With dimethylformamide as solvent and potassium carbonate as base.        BQ: In two steps, first, condensation of                                      2(chloromethyl)-4-isopropylsaccharin and benzyl                               2,6dichloro-3-hydroxybenzoate with dimethylformamide as solvent and sodiu     hydride as base and, second, debenzylation by catalytic hydrogenation ove     palladium on carbon in methanol containing acetic acid.                       BT: With tetrahydrofuran as solvent and triethylamine as base.           

EXAMPLES 43A-BY

Preparation of 2-Chloromethyl-4-isopropyl-6-methoxysaccharin

To a solution of 300 mL of N,N,N',N'-tetramethylethylenediamine (TMEDA,1.99 moles) in 4 L of anhydrous ether was added 1550 mL of sec-BuLi(1.3M) and the mixture was cooled to -70° C. under a nitrogenatmosphere. A solution of 454.2 g of2-isopropyl-4-methoxy-N,N-diethylbenzamide (1.82 moles) in 300 mL ofanhydrous ether was added dropwise over 30 minutes The temperature wasmaintained at or below -60° C. during the addition. After the additionthe mixture was stirred at -70° C. for one hour, allowed to warm to -50°C., held at -50° C. for 30 minutes, then cooled back to -70° C. Bycannulation tube a solution of 200 g of SO₂ in 200 mL of dry etherprecooled to -40° C. was added under positive nitrogen pressure over a20-minute period. The temperature of the reaction mixture during theaddition was maintained below -40° C. A white powdery precipitate ofaryllithium sulphinate separated out almost immediately. After theaddition the cooling bath was removed and the mixture was stirred atambient temperature for two hours, then cooled to -5° C. With continuedstirring 190 mL of sulfuryl chloride (2.36 moles) was added dropwiseover a 15-minute period while maintaining the temperature below 10° C.After further stirring for 30 minutes at 0°-5° C., a white insolubleprecipitate was filtered off and washed with 2 L of anhydrous ether.Removal of the solvent at atmospheric pressure afforded the resultingsulfonyl chloride (a crude dark oil) was dissolved in 1.4 L of THF. Thesolution was cooled to -10° C., and 540 mL of concentrated aqueousammonia (28%) was added in portions over 15 minutes. The temperature waskept at 15° C. or below throughout the addition. After stirring for 15minutes at ambient temperature the THF and excess ammonia were removedunder vacuum to give a dark oil, which was diluted with 6.0 L of waterand acidified with 3N HCl to pH 1. The resulting light yellow solid wascollected by filtration, washed with 800 mL of water, dried at 60° C.under vacuum for 18 hours and recrystallized from a mixture of 800 mL ofethyl acetate and 3 L of hexane to give 429 g (72%) of2-aminosulfonyl-6-isopropyl-4-methoxy-N,N-diethylbenzamide, mp 122°-125°C.

A solution of 429.6 g of the diethylbenzamide (1.31 mole) in 1.5 L ofacetic acid was refluxed for 20 hours, then cooled to room temperature.The solvent was removed under vacuum. The oily residue was dissolved in6 L of water and the pH was adjusted to 1 with 6N HCl. The crude productwas collected by filtration, washed with 2 L of water, dried at 60° C.under vacuum for 18 hours and recrystallized from ethyl acetate/hexaneto give 303 g (91%) 4-isopropyl-6-methoxysaccharin, mp 188°.

To a suspension of 24 g of paraformaldehyde (0.8 mole) and 86.4 g ofchlorotrimethylsilane (1.6 moles) in 200 mL of 1,2-dichloroethane wasadded 0.8 ml anhydrous tin(IV) chloride and the resulting solutionstirred on a steam bath for one hour. 4-Isopropyl-6-methoxysaccharin(51.4 g, 0.2 mole) was added to the clear solution and the mixture wasrefluxed for 18 hours, cooled to room temperature and poured into water.The organic layer was separated, washed with 50 mL of 2N sodiumhydroxide solution, dried over anhydrous magnesium sulfate andconcentrated under vacuum. The residue was purified by crystallizationfrom ethyl acetate/hexane to give 57 g (87%) of2-chloromethyl-4-isopropyl-6-methoxysaccharin, mp 151°.

Examples 43A-CA of compounds of formula I wherein m is 0 except Example43F wherein m is 1, R₂ is hydrogen, R₃ is isopropyl and R₄ is 6-methoxywere prepared from 2-chloromethyl-4-isopropyl-6-methoxysaccharin and ineach example the corresponding R₁ -L_(n) -H except as noted and aredescribed in TABLE I.

                                      TABLE I                                     __________________________________________________________________________                           M.p. (° C.)                                                                    Yield (%)                                      Example                                                                            R.sub.1 -L.sub.n  From    Method                                         __________________________________________________________________________    43A  (1-phenyltetrazol-5-yl)thio                                                                     Foam    83                                                                            A                                              43B  [2-(4-morpholinylethyl)tetrazol-                                                                144-145 71                                                  5-yl]thio                 B                                              43C  4-phenyl-5-thioxotetrazolin-1-yl                                                                188.5-189.5                                                                           69                                                                            C                                              43D  4-phenylsulfonyl-5-trimethyl-                                                                   175-177 32                                                  silyl-1,2,3-triazol-1-yl                                                                        C.sub.6 H.sub.12 /C.sub.6 H.sub.6                                                     D                                              43E  [5-(2-furyl)-1,3,4-oxadiazol-2-                                                                 125-127 70                                                  yl]thio           EtOH    E                                              43F  (1-phenyltetrazol-5-yl)thio                                                                     160-161.5                                                   (m = 1)           EtOH    F                                              43G  (5-phenyl-1,3,4-oxadiazol-2-                                                                    136-137.5                                                                             53                                                  yl)thio           EtOH    E                                              43H  [1-(3-succinoylaminophenyl)-                                                                    122-125 78.6                                                tetrazol-5-yl]thio                                                                              EtOH    B                                              43I  2-benzoyl-4,5-dibromoimidazol-                                                                  177-180 32                                                  1-yl              MeCN/EtOH                                                                             I                                              43J  (5-benzyl-1,3,4-oxadiazol-2-yl)-                                                                121-123 76                                                  thio              EtOH    E                                              43K  (5-hydroxy-6-methyl-6,7-dihydro-                                                                *       51                                                  1H-1,2,4-triazolo[3,4-b][1,3]-                                                                          K                                                   thiazin-3-yl)thio                                                        43L  [2-(3-pyridyl)-1,3,4-oxadiazol-5-                                                               139-141 77.6                                                yl]thio           EtOH    K                                              43M  (3-ethoxy-4-methyl-1,2,4-triazol-                                                               167-168 70                                                  5-yl)thio                 K                                              43N  [5-(4-trifluoromethylphenyl)-                                                                   201.5-203                                                                             72.7                                                1,3,4-oxadiazol-2-yl]thio                                                                       EtOH    K                                              43O  [5-(4-methoxyphenyl)-1,3,4-                                                                     138-139 85.1                                                oxadiazol-2-yl]thio                                                                             EtOH    K                                              43P  [5-(4-pyridyl)-1,3,4-oxadiazol-                                                                 184-185 45.4                                                2-yl]thio         EtOH    K                                              43Q  [5-(4-biphenylyl)-1,3,4-                                                                        153-155 78.9                                                oxadiazol-2-yl]thio                                                                             EtOH    K                                              43R  [5-(2-pyrazinyl)-1,3,4-                                                                         153-154 54.5                                                oxadiazol-2-yl]thio                                                                             EtOH/MeCN                                                                             K                                              43T  [5-(2-pyridyl)-1,3,4-                                                                           148-149 71.7                                                thiadiazol-2-yl]thio                                                                            EtOH    K                                              43U  2-thioxo-2,3-dihydro-1,3,4-                                                                     250-251 36                                                  oxadiazol-3-yl    MeCN    K                                              43V  [5-(3-furyl)-1,3,4-oxadiazol-                                                                   109-111                                                     2-yl]thio         EtOH    K                                              43W  (4-methyl-5-ethoxycarbonyl-                                                                     131-132                                                     thiazol-2-yl)thio EtOH    K                                              43X  2-thioxo-2,3-dihydro-5-(2-                                                                      275-276                                                     pyridyl)-1,3,4-thiadiazol-3-yl                                                                          K                                              43Y  (4-phenylthiazol-2-yl)thio                                                                      121-122 634.0                                                                 EtOH    K                                              43Z  (4,5-dimethylthiazol-2-yl)thio                                                                  Noncrys-                                                                              53.6                                                                  talline K                                              43AA 2,3-dihydro-2-oxo-5-phenyl-1,3,4-                                                               204-205 73                                                  thiadiazol-3-yl   MeCN    K                                              43AB [4-(4-morpholinyl)-1,2,5-                                                                       124.5-125.5                                                                           48                                                  thiadiazol-3-yl]thio                                                                            EtOH    K                                              43AC [5-(2-pyridyl)-1,3,4-oxadiazol-                                                                 161-163 64.4                                                2-yl]thio         EtOH/MeCN                                                                             K                                              43AD (3-phenyl-2-thioxo-2,3-dihydro-                                                                 112-114 73.6                                                1,3,4-thiadiazol-5-yl)thio                                                                      EtOH    AD                                             43AE 2,3-dihydro-2-oxo-5-phenyl-1,3,4-                                                               190-191 61                                                  oxadiazol-3-yl            K                                              43AF 4-(4-morpholinylsulfonyl)-3-                                                                    201-203 58                                                  trifluoromethylphenoxy                                                                          EtOH    K                                              43AG 2,5-difluoro-4-(4-morpholinyl-                                                                  171-172 46                                                  sulfonyl)phenoxy          K                                              43AH 2,6-dichloro-4-(4,5-dihydro-                                                                    176-178 50                                                  oxazol-2-yl)phenoxy                                                                             Et.sub.2 O                                                                            AH                                             43AI 4,5-dicyano-1,2,3-triazol-1-yl                                                                  163.5-165                                                                     CCl.sub.4                                                                             I                                              43AJ 2,6-dichloro-4-(2-methyltetrazol-                                                               190-192 76                                                  5-yl)phenoxy      EtOH    AH                                             43AK 4,5-dicyano-1,2,3-triazol-2-yl                                                                  185-187                                                                       C.sub.6 H.sub.6                                                                       I                                              43AL 4,5-di(t-butylsulfonyl)-1,2,3-                                                                  207.5-209                                                                             87                                                  triazol-1-yl      EtOAc   D                                              43AM 3,5-difluoro-4-(4-morpholinyl-                                                                  146-149 70                                                  carbonyl)phenoxy          K                                              43AN 3,5-difluorophenoxy                                                                             127-129 79                                                                            K                                              43AO 4,5-di(1-piperidinylcarbonyl)-                                                                  240-242 8                                                   1,2,3-triazol-1-yl        I                                              43AP 4,5-di(trifluoromethyl)-1,2,3-                                                                  200.5-202.5                                                                           71                                                  triazol-1-yl      C.sub.6 H.sub.6                                                                       D                                              43AQ 4,5-di(1-piperidinylcarbonyl)-                                                                  225-226 64                                                  1,2,3-triazol-2-yl                                                                              EtOAc   I                                              43AR 3,4-difluoro-4-(4-morpholinyl-                                                                  Glass   50                                                  sulfonyl)phenoxy          K                                              43AS 2-methylthio-5-methyl-6-oxo-1,2-                                                                200-202 41                                                  dihydro-1,2,4-triazin-1-yl                                                                              K                                              43AT [5-(3,5-dimethoxyphenyl)-1,3,4-                                                                 144-145 75                                                  oxadiazol-2-yl]thio                                                                             EtOH    K                                              43AU [5-(4,5-dimethoxyphenyl)-1,3,4-                                                                 65-80   35.7                                                oxadiazol-2-yl]thio                                                                             EtOH    K                                              43AV cyanothio         102-104 44.4                                                                  EtOH                                                   43AW (4-methyl-5-oxo-6-hydroxy-4,5-                                                                          39                                                  dihydro-1,2,4-triazin-3-yl)thio                                                                 EtOAc   AW                                             43AX 2,6-dichloro-4-ethoxycarbonyl-                                                                  oil                                                         phenoxy                   K                                              43AY (cycloheptatrienon-2-yl)oxy                                                                     148-149 47                                                                            AH                                             43AZ [5-(4-pentyloxyphenyl)-1,3,4-                                                                   113-114 65.5                                                oxadiazol-2-yl]thio                                                                             EtOH    K                                              43BA (4-ethoxycarbonylisoxazol-5-yl)-                                                                158-160 14                                                  oxy               EtOH    K                                              43BB (2,5-dioxopyrrolidin-1-yl)oxy                                                                   227-228 54                                                                    C.sub.7 H.sub.16                                                                      BB                                             43BC 2-methyl-4,5-di(hydroxymethyl)-                                                                 167-168 10                                                  3-pyridyloxy      Et.sub.2 O                                                                            K                                              43BD 2,4-dichloro-3-[2-(4-morpholinyl)-                                                              >130*   43                                                  ethoxycarbonyl]phenoxy                                                                          Et.sub.2 O                                                                            E                                              43BE 5-phenylsulfonyl-1,2,3-triazol-                                                                 164-165 25                                                  1-yl              EtOAc   D                                              43BF 2-diethylphosphonylphenoxy                                                                      104-106 27                                                                            BF                                             43BG 2,6-difluoro-4-(4-morpholinyl)-                                                                 172-174 27                                                  sulfonyl)phenoxy          K                                              43BH 2,5-difluoro-4-(4-methyl-1-                                                                     201-203 37                                                  piperazinylsulfonyl)phenoxy                                                                             BH                                             43BI 2,6-difluoro-4-(4-methyl-1-                                                                     201-203 8                                                   piperazinylsulfonyl)phenoxy                                                                             BH                                             43BJ 3-benzyloxy-4,5-dihydro-5-oxo-                                                                  155.5-157                                                                             70                                                  1,2,4-oxadiazol-4-yl      AH                                             43BK 1,2,5-thiadiazol-3-yl                                                                           107-109 39.5                                                                  EtOH    K                                              43BL {5-{4-[2-(2-methoxyethoxy)-                                                                     106-108 79.7                                                ethoxy[phenyl}-1,3,4-oxadiazol-                                                                         K                                                   2-yl}thio                                                                43BM [5-)3,4-methylenedioxyphenyl)-                                                                  162-163                                                     1,3,4-oxadiazol-2-yl]thio                                                                       EtOH/MeCN                                                                             K                                              43BN [5-(2,5-dimethoxyphenyl)-1,3,4-                                                                 124-126 71                                                  oxadiazol-2-yl]thio                                                                             EtOH    K                                              43BO (5-methoxycarbonylisoxazol-                                                                     131-132                                                     3-yl)oxy          EtOH    K                                              43BP (1-methyl-2-ethoxycarbonylindol-                                                                150-152 38.9                                                3-yl)oxy                  AH                                             43BQ [5-(2-methoxyphenyl)-1,3,4-                                                                     oil                                                         oxadiazol-2-yl]thio       K                                              43BR (50phenyloxazol-2-yl)thio                                                                       128-129                                                                       EtOH    K                                              43BS 2-(4-methoxybenzoyl)indol-1-yl                                                                  177-178 58                                                                            I                                              43BT 2-methyl-3-(2,6-dichlorobenzoyl)-                                                               268-270 86                                                  indol-1-yl        EtOAc   I                                              43BU (2-phenyl-5-methylthiazol-4-yl)oxy                                                              157-158 51                                                                    EtOH    K                                              43BV (2-methyl-5-phenylthiazol-4-yl)oxy                                                              102-103.5                                                                             11                                                                    EtOH    K                                              43BW [1-(3-pyridyl)tetrazol-5-yl]thio                                                                134-136 63.6                                                                  EtOH    K                                              43BX 2,3,5-trifluoro-4-(4-morpholinyl-                                                               170-171.5                                                                             49.3                                                sulfonyl)phenoxy  EtOH    K                                              43BY [1-(2,5-dimethoxyphenyl)tetrazol-                                                               142-143 15.8                                                5-yl]thio         EtOH    K                                              __________________________________________________________________________     A: With dimethylformamide as solvent and 1phenyltetrazole-5-thiol sodium      salt.                                                                         B: With dichoromethane as solvent and triethylamine as base.                  C: With dimethylformamide as solvent and sodium methoxide as base.            D: In two steps, first, condensation of                                       2(chloromethyl)-4-isopropyl-6-methoxysaccharin with sodium azide and a        catalytic amount of 18crown-6 ether in benzene or toluene at room             temperature and, second, cycloaddition of the resulting                       2(azidomethyl)-4-isopropylsaccharin with the corresponding acetylene, in      this exmaple phenylsulfonyltrimethylsilylacetylene, in the same solvent       with or without heating.                                                      E: With methyl ethyl ketone as solvent and potassium carbonate as base.       *Hydrochloride salt.                                                          F: In three steps by, first, condensation of the thallium salt of             4isopropyl-6-methoxysaccharin formed from 4isopropyl-6-methoxysaccharin       and thallium ethoxide with                                                    1phenyl-5-(3-chloro-3-phenylthio-propyl)tetrazole in dimethylformamide in     57% yield, second, oxidation of the resulting                                 2[3(1-phenyltetrazol-5-yl)-1-(phenylthio)propyl4-isopropyl-6-methoxysacch    rin with mchloro-perbenzoic acid in 60.5% yield and, third, thermal            elimination of the resulting 2[3(1-                                           phenyltetrazol5-yl)-1-(phenylthio)propyl4-isopropyl-6-methoxysaccharin in     75% yield.                                                                    I: With dimethylformamide as solvent and sodium hydride as base.              K: With acetonitrile as solvent and methyltriazabicyclodecene as base.        *Mixture (1:1) of geometric isomers.                                          AD: With methyl ethyl ketone as solvent and                                   3phenyl-2-thioxo-2,3-dihydro-1,3,4-thiadiazol-5-thiol potassium salt.         AH: With dimethylformamide as solvent and potassium carbonate as base.        AV: With acetone as solvent and potassium thiocyanate.                        AW: With dimethylformamide as solvent and diisopropylethylamine as base.      BB: With acetonitrile as solvent and diisopropylethylamine as base.           BF: With tetrahydrofuran as solvent and potassium tbutoxide as base.          BH: With acetonitriledimethylformamide as solvent and                         methyltriazabicyclodecene as base.                                       

EXAMPLE 44

A solution of 2-chloromethyl-4-ethyl-5,7-dimethoxysaccharin (Example22L, 0.4 g) and 1-phenyltetrazol-5-thiol sodium salt (0.28 g) indimethylformamide (3 mL) was heated at 110° C. for two hours, thenpoured into water. Recrystaliization of the resulting solid fromethanol-water afforded2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethyl-5,7-dimethoxysaccharin, 0.44g, 74% yield, mp 162°-164° C.

EXAMPLE 45

A. A solution of 5-chloro-2-benzyl-2H-isothiazol-3-ono-1-oxide (Example26A, 1.50 g) and 1-methoxy-3-trimethylsilyloxybutadiene (d=0.885, 1.30mL) was heated in a pressure tube at 65° C. overnight. More1-methoxy-3-trimethylsilyloxybutadiene (0.74 mL) was added and thesolution was again heated in a pressure tube at 65° C. overnight thenstripped of volatiles. Dichloromethane was added, the mixture wasstripped of volatiles, and the addition and stripping were repeated,finally under high vacuum. Dichloromethane was added to the golden amberoil, which solidified after several hours affording2-benzyl-6-hydroxy-1,2-benzisothiazol-(1H)-3-one-1-oxide (1.16 g, 68%yield).

B. A solution of2-benzyl-6-hydroxy-1,2-benzisothiazol-(1H)-3-one-1-oxide (3.75 g) inmethanol (75-100 mL) was added dropwise to a solution ofo-monoperphthalic acid magnesium salt (8.14 g) in water (70-100 mL) atroom temperature. Methanol was (200-250 mL) added to dissolve theresulting precipitate, and the solution was stirred overnight at roomtemperature. An equal volume of water was added, and the mixture wasextracted with dichloromethane. The dichloromethane extract was washedwith water and saturated aqueous sodium chloride solution, dried oversodium sulfate and stripped of dichloromethane. A solution of theresulting solid (4.17 g) in dichloromethane was washed with water andsaturated aqueous sodium chloride solution, dried over sodium sulfateand stripped of dichloromethane, affording 2-benzyl-6-hydroxysaccharin(3.87 g, 98% yield).

C. A mixture of 2-benzyl-6-hydroxysaccharin (0.86 g), 2-bromoethyl2-methoxyethyl ether (d=1.347, 0.45 mL), potassium carbonate (1.24 g),methyl ethyl ketone (50 mL) and dimethylformamide (2 mL) was heatedunder reflux for five hours, then poured into ice-water (500 mL). Theresulting solid was collected, washed with water and dried affording2-benzyl-6-[2-(2-methoxyethoxy)ethoxy]saccharin (0.92 g, 78% yield, mp86°-88° C.).

D. A mixture of 2-benzyl-6-[2-(2-methoxyethoxy)ethoxy]saccharin (2.05g), methanol (75-100 mL), ammonium formate (1.10 g) and palladium oncarbon (10%, 1.0 g) was heated under reflux for 40 minutes, allowed tocool and filtered. The filtrate was stripped of volatiles affording6-[2-(2-methoxyethoxy)-ethoxy]saccharin ammonium salt, a mixture ofwhich with chloromethyl phenyl sulfide (0.79 g) and dimethylformamidewas heated for eight hours at 100° C., stirred overnight at roomtemperature, and poured into ice-water (600 mL). The resulting mixturewas extracted with dichloromethane. The dichloromethane extract waswashed with water and saturated aqueous sodium chloride solution, driedover sodium sulfate and stripped of dichloromethane. Columnchromatography of the residue (1.70 g) on silica gel usingdichloromethane-acetone (98:2) as eluant and again usingdichloromethane-acetone (99:1) as eluant afforded2-phenylthiomethyl-6-[2-(2-methoxyethoxy)-ethoxy]saccharin (0.96 g, 45%yield).

E. Sulfuryl chloride (0.34 g) was added dropwise with stirring to asolution of 2-phenylthiomethyl-6-[2-(2-methoxyethoxy) ethoxy]saccharin(0.96 g) in dichloromethane. Stirring was continued at room temperaturefor three hours and the solution was stripped of volatiles.Dichloromethane was added and the solution was stripped again. Hexanewas added to the residue and the mixture was stirred at room temperatureovernight. The resulting white solid was collected and dried affording2-chloromethyl-6-[2-(2-methoxyethoxy)-ethoxy]saccharin (0.69 g, 89%yield, mp 113°-115° C.).

F. By a method similar to that of Example 44 condensation of2-chloromethyl-6-[2-(2-methoxyethoxy)ethoxy]saccharin (34 g.) and1-phenyltetrazol-5-thiol sodium salt (0.19 g) in methyl ethyl ketone at60° C. and purification of the product (470 mg) by column chromatographyon silica gel first with dichloromethane and then withdichloromethane-acetone (up to 97:3) as eluant afforded2-(1-phenyltetraol-5-yl)thiomethyl-6-[2-(2-methoxyethoxy)ethoxy]saccharinas an oil (390 g, 82% yield).

EXAMPLE 46

A solution of 2-(5-phenyl-1-tetrazolyl)thiomethyl-4-ethylsaccharin(Example 30AE, 0.020 g) and 1-phenyltetrazol-5-thiol sodium salt (0.0026g) in dimethylformamide (1 mL) was heated at 100° C. for three days,then poured into water. Recrystallization of the resulting solid fromethanol-water afforded2-(4-phenyl-5-thioxo-1-tetrazolyl)methyl-4-ethylsaccharin, 0.012 g, 60%yield, mp 127°-129° C.

EXAMPLE 47

A. By the method of Example 22A3,4-dimethoxy-2-propyl-N,N-dimethylbenzamide (9.2 g) wasaminosulfonylated with sulfur dioxide and hydroxylamine-O-sulfonic acid(5.6 g) to give2-aminosulfonyl-4,5-dimethoxy-6-propyl-N,N-dimethylbenzamide (7.4 g, 63%yield), which was cyclized in quantititive yield to4-propyl-5,6-dimethoxysaccharin, phenylthiomethylation of which withchloromethyl phenyl sulfide (1.42 mL) gave2-phenylthiomethyl-4-propyl-5,6-dimethoxy-saccharin (4.07 g), reactionof part (3.59 g) of which with sulfuryl chloride (2.12 mL) gave2-chloromethyl-4-propyl-5,6-dimethoxysaccharin, 2.84 g, 97% yield.

B. By the method of Example 44 condensation of2-chloromethyl-4-propyl-5,6-dimethoxysaccharin (0.6 g) and1-phenyltetrazol-5-thiol sodium salt (0.36 g) in dimethylformamide (5mL) and purification of the product by column chromatography on silicagel using ethyl acetate-hexane (3:7) as eluant followed by triturationwith hexane afforded2-(1-phenyltetrazol-5-yl)thiomethyl-4-propyl-5,6-dimethoxysaccharin,0.65 g, 76% yield, mp 145°-146° C.

EXAMPLE 48

A. By the method of Example 22A2-aminosulfonyl-4,5-dimethoxy-6-isopropyl-N,N-dimethylbenzamide (10.75g) was prepared and cyclized to 4-isopropyl-5,6-dimethoxysaccharin (top186°-188° C. from ether-hexane), phenylthiomethylation of part (5 g) ofwhich with chloromethyl phenyl sulfide (2.48 mL) gave2-phenylthiomethyl-4-isopropyl-5,6-dimethoxysaccharin (4.07 g), reactionof which with sulfuryl chloride (three molar equivalents) gave2-chloromethyl-4-isopropyl-5,6-dimethoxysaccharin, 85% yield, mp117°-119° C. from ethyl acetate-hexane.

B. By the method of Example 44 condensation of2-chloromethyl-4-isopropyl-5,6-dimethoxysaccharin (1.4 6 g) and1-phenyltetrazol-5-thiol sodium salt (0.92 g) in dimethylformamide (5mL) and recrystallization of the product from ethanol-water afforded2-(1-phenyltetrazol-5-yl)thiomethyl-4-isopropyl-5,6-dimethoxy-saccharin, 1.05 g, 51% yield, mp69°-71° C.

EXAMPLE 49

A. Ethanethiol (43.9 g) was added with stirring to a suspension ofaluminum chloride (62.74 g) in chloroform (500 mL) at 0° C. To theresulting solution was added a solution of4-isopropyl-6-methoxysaccharin (20.0 g) in chloroform (550 mL) during 30minutes. The resulting solution was warmed to and maintained at 60° C.for 3-4 hours, then poured into ice-water acidified with hydrochloricacid. The resulting solid was collected by filtration, washed with waterand dried affording 4-isopropyl,6-hydroxysaccharin, 18.4 g., 97% yield.

B. By the method of Example 21 phenylthiomethylation of4-isopropyl-6-hydroxysaccharin (0.004 mole) with chloromethyl phenylsulfide (0.61 mL) gave2-phenylthiomethyl-4-isopropyl-6-hydroxy-saccharin (0.32 g, 21% yield),reaction of which with sulfuryl chloride (0.73 g) gave2-chloromethyl-4-isopropyl-6-hydroxysaccharin, 84% yield, mp 149°-150°C.

C. By the method of Example 44 condensation of2-chloromethyl-4-isopropyl-6-hydroxysaccharin (0.3 g) and1-phenyltetrazol-5-thiol sodium salt (0.23 g) in dimethyl formamide (10mL) and flash chromatography of the resulting product on silica gelusing hexane-ethyl acetate (7:3) as eluant afforded2-(1-phenyl-tetrazol-1-yl) thiomethyl-4-isopropyl-6-hydroxy-saccharin,0.3 g, 67% yield, mp 188.5°-189.5° C.

EXAMPLE 50

A. A solution of 5-chloro-2-benzyl-2H-isothiazol-3-one-1-oxide (Example26A, 5.8 g) and 2-ethoxyfuran (3.76 g) in benzene (40 mL) was heated to50° C. More benzene (30 mL) was added to the solidified react ionmixture, which was then heated under reflux for 15 minutes, then at 70°C. for 45 minutes, then chilled overnight in the refrigerator. Theresulting pale yellow solid was collected, washed with cold benzene anddried affording2-benzyl-4-ethoxy-7-hydroxy-1,2-benzisothiazol-(1H)-3-one-1-oxide, 3.05g, 40% yield.

B. m-Chloroperbenzoic acid (8.6 g) was added with stirring to solutionof 2-benzyl-4-ethoxy-7-hydroxy-1,2-benzisothiazol-(1H)-3-one-1-oxide(7.9 g) in dichloromethane (about 500 mL) and methanol (31 mL). Stirringwas continued for several hours, more m-chloroperbenzoic acid (8.6 g)was added and stirring was continued for several days. Dichloromethanewas added. The solution was washed with water. The solid which separatedwhen the solution was washed again with water was collected (2.33 g, mp196°-199° C.). More solid separated when the dichloromethane layer waswashed with saturated aqueous sodium chloride solution and was collected(4.10 g, mp 196°-199° C.). Both solids were determined to be2-benzyl-4-ethoxy-7-hydroxysaccharin.

C. A mixture of 2-benzyl-4-ethoxy-7-hydroxysaccharin (1.0 g), allylbromide (0.36 g), potassium carbonate (0.62 g) and methyl ethyl ketone(about 20 mL) was heated at 80° C. for one hour. More allyl bromide(0.36 g) was added and heating at 80° C. was continued for one andone-half hours. The mixture was cooled and poured into ice-water (500mL). The solid was collected affording2-benzyl-4-ethoxy-7-allyloxysaccharin, 1.08 g, 96% yield, mp 148°-149°C.

D. A mixture of 2-benzyl-4-ethoxy-7-allyloxysaccharin (0.25 g) andtriglyme was heated at 200° C. for 20 minutes, examined for extent ofreaction by thin layer chromatography, heated at 200° C. for 20 minutesmore, stirred overnight and poured into ice-water. The resulting tacky,brown solid was dissolved in dichloromethane. The dichloromethanesolution was washed with saturated aqueous sodium chloride solution,dried over sodium sulfate and stripped of dichloromethane. Columnchromatography of the residue (0.29 g) on silica using dichloromethaneand dichloromethane-acetone (up to 99:1) as eluants afforded2-benzyl-4-ethoxy-6-allyl-7-hydroxysaccharin (90 mg, 36% yield) whosemass spectrogram showed a molecular ion at mass 373.

E. A mixture of 2-benzyl-4-ethoxy-6-allyl-7-hydroxysaccharin (2.45 g),potassium carbonate (2.76 g) and methyl iodide (1.84 g) in acetone washeated at 50° C. with stirring for two hours, then poured with stirringinto ice-stirring water (500 mL). The resulting gooey precipitatecrystallized overnight affording2-benzyl-4-ethoxy-6-allyl-7-methoxysaccharin, 2.35 g, 92% yield, mp92°-94° C.

F. By the method of part D of Example 452-benzyl-4-ethoxy-6-allyl-7-methoxysaccharin (2.35 g) was simultaneouslydebenzylated and hydrogenated with ammonium formate (1.51 g) andpalladium on carbon (10%, 1.25 g) in methanol (70-100 mL) affording4-ethoxy-6-propyl-7-methoxysaccharin ammonium salt (1.94 g),phenylthiomethylation of which with chloromethyl phenyl sulfide (0.95 g)in dimethylformamide and purification of the product (a yellow oil, 2.67g) by column chromatography on silica gel using dichloromethane-hexane(80:20) as eluant afforded2-phenylthiomethyl-4-ethoxy-6-propyl-7-methoxysaccharin, 0.85 g, 34%yield.

G. By the method of part E of Example 452-phenylthiomethyl-4-ethoxy-6-propyl-7-methoxysaccharin (0.85 g) wasreacted with sulfuryl chloride (0.30 g) in dichloromethane and purifiedwith hexane affording2-chloromethyl-4-ethoxy-6-propyl-7-methoxysaccharin, 0.62 g, 89% yield,mp 131°-133° C.

H. By the method of part F of Example 45 condensation of2-chloromethyl-4-ethoxy-6-propyl-7-methoxysaccharin (0.62 g) and1-phenyltetrazol-5-thiol sodium salt (0.36 g initially and a smallamount more after 3.5 hours reaction time, total reaction time 8 hours)and isolation of the oily product by extraction with dichloromethane andpurification thereof first by column chromatography on silica gel usingdichloromethane as eluant and then by crystallization of the resultingoil (0.62 g., 71% yield) from ethanol gave2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-6-propyl-7-methoxysaccharin,mp 110°-111° C.

EXAMPLE 51

A. s-Butyllithium (0.87M in cyclohexane, 20.4 mL) was added dropwiseduring one hour with stirring at -78° C. to a solution of4-ethyl-5,7-dimethoxysaccharin (Example 22L, 2.2 g) in tetrahydrofuran(100 mL). After continued stirring at -78° C. for one hour methyl iodide(1.5 mL) was added. Stirring was continued at -78° C. for 15 minutes,the temperature was allowed to rise to room temperature, and the mixturewas quenched in water. Aqueous sodium hydroxide (0.5%, 200 mL) wasadded. The mixture was washed with ethyl acetate (200 mL), acidifiedwith concentrated hydrochloric acid and extracted with ethyl acetate(200 mL). The ethyl acetate extract was washed with aqueous sodiumthiosulfate (10%, 50 mL) and saturated aqueous sodium chloride (50 mL),dried over sodium sulfate and stripped of ethyl acetate affording4-ethyl-5,7-dimethoxy-6-methylsaccharin (0.73 g, 32% yield).

B. By the method of Example 21 phenylthiomethylation of4-ethyl-5,7-dimethoxy-6-methylsaccharin (0.65 g) with chloromethylphenyl sulfide (0.24 mL) gave2-phenylthiomethyl-4-ethyl-5,7-dimethoxy-6-methylsaccharin, reaction ofwhich with sulfuryl chloride gave2-chloromethyl-4-ethyl-5,7-dimethoxy-6-methylsaccharin, 0.16 g, 22%yield.

C. By the method of Example 44 condensation of2-chloromethyl-4-ethyl-5,7-dimethoxy-6-methylsaccharin (0.17 g) and1-phenyltetrazol-5-thiol sodium salt (0.084 g) in dimethylformamide (4mL) and purification of the product by flash column chromatography onsilica gel using hexane-ethyl acetate (75:25) as eluant afforded2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethyl-5,7-dimethoxy-6-methylsaccharin, 0.15 g, 76% yield,mp 44°-46° C.

EXAMPLE 52

A. A mixture of 2-benzyl-4-ethoxy-7-hydroxysaccharin (part B of Example50, 0.5 g), t-butyl bromoacetate (0.3 g, 0.25 mL), potassium carbonate(0.30 g) and methyl ethyl ketone (about 10 mL) was heated at 70°-80° C.for about one hour, let cool and poured into ice-water (400 mL). Themixture was stirred overnight and the solid was collected affording2-benzyl-4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin, 0.58 g, 86%yield.

B. By the method of part D of Example 45 in two successive preparations2-benzyl-4-ethoxy-7-(t-butoxycarbonylmethoxy) saccharin (0.5 g, 6.5 g)was debenzylated with ammonium formate (0.25 g, 3.66 g) and palladium oncarbon (10%, 0.25 g, 2 g) in methanol affording4-ethoxy-7-(t-butoxycarbonylmethoxy) saccharin ammonium salt (0.44 g,5.63 g), phenylthiomethylation of which with chloromethyl phenyl sulfide(0.2 g, 2.38 g) in dimethylformamide and purification of the combinedproducts (0.46 g, 6.42 g) by column chromatography on silica gel usingdichloromethane and dichloromethane-acetone (98:2) as eluants afforded2-phenylthiomethyl-4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin, 1.92g, 40% yield.

C. By the method of part E of Example 452-phenylthiomethyl-4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin (1.92g) was reacted with sulfuryl chloride (0.54 g) in dichloromethane atabout 5° C. and purified with hexane affording2-chloromethyl-4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin, 1.54 g,95% yield, mp 117°-119° C.

D. By the method of part F of Example 45 condensation of2-chloromethyl-4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin (1.42 g)and 1-phenyltetrazol-5-thiol sodium salt (0.70 g initially and a smallamount more after 6 hours reaction time, total reaction time 8 hours)and isolation of the product (1.20 g) by extraction with dichloromethaneand purification of part (0.42 g) thereof by column chromatography onsilica gel using dichloromethane-acetone (up to 98:2) as eluant afforded2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin, 300 mg, 71%yield, mp 110°-112° C.

EXAMPLE 53

A solution of2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-7-(t-butoxycarbonylmethoxy)saccharin(Example 52, 0.47 g) in trifluoroacetic acid (5-10 mL) anddichloromethane (5-10 mL) was stirred at room temperature for two hours,then stripped of volatiles, then stripped three times more fromdichloromethane, then stripped once more from acetone. A solution of theresidual oil in acetone (1 mL) was added to ice-water (100 mL)containing concentrated hydrochloric acid (1 mL). The resulting solidwas collected, washed with water and dried (0.34 g). A solution thereofin dichloromethane was eluted through silica gel in a 15-mL sinteredglass funnel with chloroform-methanol (95:5) affording2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-7-carboxymethoxysaccharin,70 mg, 17% yield, mp 187°-189° C.

EXAMPLE 54

A. Bromination of 1,2-dimethoxy-4-isopropylbenzene (31 g) withN-bromosuccinimide on Kieselgel in tetrachloridemethane by the method ofHisatoshi et al. (Bulletin of the Chemical Society of Japan, vol. 32,pp. 591°-593, 1989) gave 5-bromo-1,2-dimethoxy-4-isopropylbenzene,lithiation of which with n-butyllithium in ether gave5-lithio-1,2-dimethoxy-4-isopropylbenzene, diethylaminocarbonylation ofwhich in the same solvent gave2-isopropyl-4,5-dimethoxy-N,N-diethylbenzamide (15.2 g) as a viscousoil.

B. By the method of Example 43 aminosulfonylation of this2-isopropyl-4,5-dimethoxy-N,N-diethylbenzamide with s-butyllithium,sulfur dioxide, sulfuryl chloride and concentrated ammonia gave2-isopropyl-4,5-dimethoxy-6-aminosulfonyl-N,N-diethylbenzamide (4.5 g,mp 181°-182° C.), cyclization of which in acetic acid gave4-isopropyl-6,7-dimethoxysaccharin, 2.86 g, mp 210°-212° C.

C. Diisopropylethylamine (0.5 mL) was added to a solution of4-isopropyl-6,7-dimethoxysaccharin (0.5 g) in dimethylformamide (3 mL).After 15 minutes chloromethyl phenyl sulfide (0.35 g) was added Themixture was heated at 80° C. for 16 hours, diluted with ethyl acetate,washed with aqueous sodium carbonate solution, hydrochloric acid (3N)and saturated aqueous sodium chloride solution, dried over sodiumsulfate, and stripped of solvents. Purification of the residue by flashchromatography on silica gel using dichloromethane as eluant gave2-phenylthiomethyl-4-isopropyl-6,7-dimethoxysaccharin (0.35 g),chlorination of which with sulfuryl chloride (0.1 mL) in dichloromethane(3 mL) and purification of the product by trituration with hexane gave2-chloromethyl-4-isopropyl-6,7-dimethoxysaccharin, 0.3 g.

D. By a method similar to that of Example 4 4 condensation of2-chloromethyl-4-isopropyl-6,7-dimethoxysaccharin (0.095 g) and1-phenyltetrazol-5-thiol sodium salt (0.120 g) in acetonitrile (2 mL)and purification of the product by crystallization from ethanol afforded2-(1-phenyltetrazol-5-yl)thiomethyl-4-isopropyl-6,7-dimethoxy-6-methylsaccharin,0.099 g, 70% yield, mp 169°-171° C.

EXAMPLE 55

A. By the methods of parts D and E of Example 45 debenzylation of2-benzyl-4-ethoxy-7-hydroxysaccharin (part B of Example 50) withammonium formate and palladium on carbon in methanol gave4-ethoxy-7-hydroxysaccharin ammonium salt, phenylthiomethylation ofwhich with chloromethyl phenyl sulfide in dimethylformamide gave2-phenylthiomethyl-4-ethoxy-7-hydroxysaccharin, reaction of which withsulfuryl chloride in dichloromethane gave2-chloromethyl-4-ethoxy-7-hydroxysaccharin.

B. By the method of part F of Example 45 condensation of2-chloromethyl-4-ethoxy-7-hydroxysaccharin (1.95 g) and1-phenyltetrazol-5-thiol sodium salt (1.5 g, reaction time about 8hours) and purification of part of the product (2.5 g., 88% yield) fromethanol gave 2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-7-hydroxysaccharin, mp 178°-180° C.

EXAMPLE 56

A mixture of2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-7-hydroxysaccharin (Example55, 0.5 g), dimethylcarbamyl chloride (0.14 mL, 0.16 g),diazabicyclooctane (0.27 g) and N,N-dimethylacetamide (20 mL) was heatedat 80° C. for 4-5 hours, cooled and poured with stirring into ice-water(400 mL). Column chromatography of the resulting solid on silica gel byelution with dichloromethane and dichloromethane-acetone (up to 98:2 )gave first2-(4-phenyl-5-thioxo-1-tetrazolyl)methyl-4-ethoxy-7-dimethylaminocarbonylsaccharin(mp 172°-173° C. after recrystallization from ethanol) and then2-(1-phenyltetrazol-5-yl)thiomethyl-4-ethoxy-7-dimethylaminocarbonyloxysaccharin(top 145°-146° C. after sonication in ether).

EXAMPLE 57

2-(1-phenyltetrazol-5-yl)thiomethyl-4-isopropyl-5,6-dimethoxy-saccharin(0.48 g) was added with stirring at 0° C. to a solution of aluminumchloride (0.4 g) and ethanethiol (0.15 mL) in chloroform (3 mL). Thetemperature was allowed to rise to and remain at room temperature for 18hours. The reaction mixture was passed through silica gel with ethylacetate-hexane (2:3) as eluant affording as a colorless oil2-(1-phenyltetrazol-5-yl)thiomethyl-4-isopropyl-5-hydroxy-6-methoxy-saccharin,0.3 g, 77% yield, whose structure was proven by proton and carbon-13magnetic resonance, mass spectrometric and nuclear Overhauserenhancement analyses. The latter analysis showed 19% enhancement of themethoxy protons signal and 10% enhancement of the C-7 proton signal.

BIOLOGICAL TEST RESULTS

In the test of elastase inhibition using human leukocyte elastasedescribed above at pages 89-90 the compounds of formula I of Examples41-57 showed K_(i) * values in the range from 0.024 nM (Example 43AL) to1000 nM (Example 42D, for example).

ADDITIONAL BACKGROUND OF THE INVENTION

Additional Information Disclosure Statement

Dunlap et al. PCT Application WO 90/13549 published Nov. 15, 1990describes saccharin derivatives useful as proteolytic enzyme inhibitorshaving the structural ##STR4## wherein: L is --O--, --S--, --SO-- or--SO₂ --;

m and n are each independently 0 or 1;

R₁ is halogen, lower-alkanoyl, 1-oxo-phenalenyl, phenyl (or phenylsubstituted by halogen, lower-alkyl, lower-alkoxy, nitro, amino,lower-alkylamino or di-lower-alkyl-amino) or heterocyclyl selected from1H-(5-tetrazolyl), 5-oxo-1-tetrazolyl, 5-thioxo-1-tetrazolyl (when R₂ asdefined hereinbelow is other than phenylthio), pyrimidinyl,2-benzoxazolyl, 2-benzothiazolyl, 2-phthalimidyl,2-(1,3,4-thiadiazolyl), 5-(1,2,4-thiadiazolyl),5-thioxo-3-(1,2,4-thiadiazolyl), 4-(5-oxo-1,3,4-thiadiazolyl),4-5-thioxo-1,3,4-thiadiazolyl), 3-(1,2,4-triazolyl),4-(1,2,4-triazolyl), (1,2,3-triazolyl), 2-imidazolyl or3-(1,2,4-triazolo[4,3-a]-pyridinyl), or such heterocyclyl groupssubstituted on any available nitrogen atom by lower-alkyl,hydroxy-lower-alkyl, cycloalkyl, 2-, 3- or 4-pyridinyl,carboxy-lower-alkyl, lower-alkoxy-carbohnyl-lower-alkyl,aminocarbonyl-lower-alkyl, lower-alkylaminocarbonyl-lower-alkyl,di-lower-alkylamino-carbonyl-lower-alkyl, amino-lower-alkyl,lower-alkylamino-lower-alkyl, di-lower-alkylamino-lower-alkyl,4-morpholinyl-lower-alkyl, 1-piperidinyl-lower-alkyl,1-pyrrolidinyl-lower-alkyl or phenyl (or phenyl substituted by amino,lower-alkylamino, di-lower-alkylamino, lower-alkanamido,N-lower-alkyl-lower-alkanamido, carboxy-lower-alkanamido, carboxy,carbo-lower-alkoxy, lower-alkoxy or halogen), or such heterocyclylgroups substituted on any available carbon atom by nitro, lower-alkyl,amino, lower-alkylamino, di-lower-alkylamino, cycloalkylamino, mercapto,lower-alkylthio, amino-lower-alkylthio,lower-alkylamino-lower-alkylthio, di-lower-alkyl-amino-lower-alkylthio,4-morpholinyl-lower-alkylthio, 1-piperidinyl-lower-alkylthio,1-pyrrolidinyl-lower-alkylthio, carbo-lower-alkoxy or phenyl (or phenylsubstituted by amino, lower-alkylamino, di-lower-alkylamino,lower-alkanamido, N-lower-alkyl-lower-alkanamido, lower-alkyl,lower-alkoxy or halogen);

R₂ is hydrogen, carbo-lower-alkoxy, phenyl or phenylthio;

R₃ is hydrogen, halogen, primary or secondary lower-alkyl, lower-alkoxy,carbo-lower-alkoxy, phenyl, fluoro-lower-alkyl, lower-alkenyl or cyano;

R₄ is hydrogen or from one to two substituents selected from halogen,cyano, nitro, amino, lower-alkanamido, phenyl-lower-alkanamido,diphenyl-lower-alkanamido, lower-alkylsulfonylamino,polyfluoro-lower-alkylsulfonylamino, aminosulfonyl, lower-alkyl,polyhalo-lower-alkyl, cycloalkyl, polyhalo-lower-alkoxy, hydroxy,lower-alkoxy, carboxy, hydroxymethyl, formyl, aminomethyl,lower-alkylsulfonyl, polyhalo-lower-alkylsulfonyl,lower-alkylsulfonyl-aminosulfonyl andlower-alkoxypoly-lower-alkyleneoxy; and wherein the --CHR₂ -- group isalways appended either to a hetero atom of the L moiety as defined aboveor it is appended to a hetero atom of the R₁ moiety, with the provisosthat (i) when m and n are 0 and R₂, R₃ and R₄ are all hydrogen, R₁cannot be halogen; (ii) when m is 0, n is 1, L is--S-- and R₂, R₃ and R₄are each hydrogen, R₁ cannot be 1-phenyl-1H-(5-tetrazolyl); (iii) when mis 0, n is 1, L is --O-- or --S-- and R₂, R₃ and R₄ are all hydrogen, R₁cannot be lower-alkanoyl; (iv) when m is 0, n is 1, L is --O--, --S-- or--SO--, and R₂, R₃ and R₄ are all hydrogen, or when m is O, n is 1, L is--S--, R₂ and R₄ are hydrogen and R₃ is halogen, or when m is 0, n is 1,L is --SO-- or --SO₂ --, R₂ is carbo-lower-alkoxy and R₃ and R₄ are bothhydrogen, R₁ cannot be phenyl or substituted phenyl.

In the following claims "corresponding" means that a variable of thestructural formula of claim 1 (formula I above) which is repeated inanother formula has the same meaning in the other formula as it has inthe formula of claim 1 unless otherwise stated and that "substitutedphenyl" and "substituted heterocyclyl" mean phenyl and heterocyclylsubstituted as defined in claim 1.

We claim:
 1. A compound having the formula ##STR5## wherein:heterocyclyl selected from 1H-(5-tetrazolyl), 5-oxo-1-tetrazolinyl,5-thioxo-1-tetrazolinyl when R₂ as defined hereinbelow is other thanphenylthio; pyimidinyl, 2-benzoxazolyl, 2-benzothiazolyl,2-phthalimidyl, 2-(1,3,4-thiadiazolyl), 5-(1,2,4-thiadiazolyl),5-thioxo-3-(1,2,4-thiadiazolinyl), 4-(5-oxo-1,3,4-thiadiazolinyl),4-(5-thioxo-1,3,4-thiadiazolinyl), 3-(1,2,4-triazolyl),4-(1,2,4-triazolyl), 1,2,3-triazol-1-yl, 2-imidazolyl,3-(1,2,4-triazolo[4,3-a]pyridinyl), pyridazin-3-yl, 4-pyron-3-yl,quinolin-8-yl, 1,3,4-oxadiazol-2-yl, coumarin-7-yl, saccharin-6-yl,imidazol-2-yl, 1,3,4-triazol-2-yl, thiazol-2-yl,2-thioxo-2,3-dihydro-1,3,4-oxadiazol-3-yl, 1,2,5-thiadiazol-3-yl,2-thioxo-2,3-dihydro-1,3,4-thiadiazol-3-yl,2-thioxo-2,3-dihydro-1,3,4-thiadiazol-5-yl, 1,2,3-triazol-2-yl,1,2,4-triazin-5-yl, 5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-yl,isoxazol-5-yl, isoxazol-3-yl, 5-oxo-1,2,4-oxadiazol-4-yl,1,1,3-trioxo-tetrahydro-1,2,5-thiadiazol-2-yl,6,7-dihydro-1H-1,2,4-triazolo[3,4-b][1,3]thiazin-3-yl,4,5-dihydro-5-oxo-1,2,4-oxadiazol-4-yl, 2,5-dioxopyrrolidin-1-yl,3-indolyl, oxazol-2-yl, thiazol-4-yl,2,3-dihydro-2-oxo-5-phenyl-1,3,4-thiadiazol-3-yl and2,3-dihydro-2-oxo-5-phenyl-1,3,4-oxadiazol-3-yl,or said heterocyclylsubstituted on any available nitrogen atom by lower-alkyl,hydroxy-lower-alkyl, cycloalkyl, 2-, 3- or 4-pyridinyl,carboxy-lower-alkyl, lower-alkoxycarbonyl-lower-alkyl,aminocarbonyl-lower-alkyl, lower-alkylaminocarbonyl-lower-alkyl,di-lower-alkylamino-carbonyl-lower-alkyl, amino-lower-alkyl,lower-alkylamino-lower-alkyl, di-lower-alkyl-amino-lower-alkyl,4-morpholinyl-lower-alkyl, 1-piperidinyl-lower-alkyl,1-pyrrolidinyl-lower-alkyl or phenyl or phenyl substituted by amino,lower-alkyl-amino, di-lower-alkylamino, lower-alkanamido,N-lower-alkyl-lower-alkanamido, carboxy-lower-alkanamido, carboxy,lower-alkoxycarbonyl, lower-alkoxy, halo or carboxy-lower-alkanoylamino,or said heterocyclyl substituted on any available carbon atom by nitro,lower-alkyl, amino, lower-alkylamino, di-lower-alkylamino,cycloalkylamino, mercapto, lower-alkylthio, amino-lower-alkylthio,lower-alkylamino-lower-alkylthio, di-lower-alkyl-amino-lower-alkylthio,4-morpholinyl-lower-alkylthio, 1-piperidinyl-lower-alkylthio,1-pyrrolidinyl-lower-alkylthio, lower- alkoxycarbonyl,di-lower-alkylamino-lower-alkyl, 4-morpholinyl-lower-alkylamino, cyano,1-piperidinyl-lower-alkyl, hydroxy-lower-alkyl, phenylsulfonyl,toluenesulfonyl, halo, tri-lower-alkylsilyl, carboxy or alkali metalsalt thereof, furyl, trifluoromethyl, 2-benzothiazolyl,lower-alkylsulfonyl, aminocarbonyl, benzyl, 4-morpholinyl, pyridinyl,lower-alkoxy, pyrazinyl, lower-alkoxycarbonyl-lower-alkyl,di-lower-alkylaminosulfonyl, 4-morpholinylcarbonyl, lower alkanoyl,benzyloxy, hydroxy, benzoyl or benzoyl substituted by lower-alkoxy orhalo, or phenyl or phenyl substituted by amino, lower-alkylamino,di-lower-alkylamino, lower-alkanamido, N-lower-alkyl-lower-alkanamido,lower-alkyl, lower-alkoxy, halo, trifluoromethyl,lower-alkoxy-poly-lower-alkoxy, methylenedioxy or lower alkoxycarbonyl;R₂ is hydrogen, lower-alkoxycarbonyl, phenyl or phenylthio; R₃ ishydrogen, halo, primary or secondary lower-alkyl, lower-alkoxy,lower-alkoxycarbonyl, phenyl, fluoro-lower-alkyl, lower-alkenyl, cyanoor di-lower-alkylamino; and R₄ is hydrogen or from one to threesubstituents selected from halo, cyano, nitro, amino, lower-alkanamido,phenyl-lower-alkanamido, diphenyl-lower-alkanamido,lower-alkylsulfonylamino, polyfluoro-lower-alkylsulfonylamino,aminosulfonyl, lower-alkyl, polyhalo-lower-alkyl, cycloalkyl,polyhalo-lower-alkoxy, hydroxy, lower-alkoxy, carboxy, hydroxymethyl,formyl, aminomethyl, lower-alkylsulfonyl, polyhalo-lower-alkylsulfonyl,lower-alkylsulfonyl-aminosulfonyl, lower-alkoxy-lower-alkoxy,lower-alkoxy-poly-lower-alkyleneoxy, carboxy-lower-alkoxy,lower-alkoxycarbonyl-lower-alkoxy or di-lower-alkylaminocarbonyloxy. 2.A compound according to claim 1 wherein R₃ is other than hydrogen and R₁is a leaving group, the acid form of which has a pKa value less thanabout
 7. 3. A compound according to claim 1 wherein R₁ is heterocyclylor substituted heterocyclyl, R₂ is hydrogen, R₃ is hydrogen orlower-alkyl and R₄ is hydrogen or lower-alkoxy.
 4. A compound accordingto claim 3 whereinR₁ is 4-phenyl-5-thioxotetrazolin-1-yl,4-(4-carboxyphenyl)-5-thioxotetrazolin-1-yl,4-(3-pyridyl)-5-thioxotetrazolin-1-yl, 2-methyl-5-thioxotetrazolin-1-yl,2-methylthio-5-thioxo-1,3,4-thiadiazolin-4-yl, 2-phthalimidyl,4-phenyl-5-oxotetrazolin-1-yl,5-[2-(1-piperidinyl)ethylthio]-2-thioxo-1,3,4-thiadiazolin-3-yl,4,5-dicyanoimidazol-1-yl, 1,1,3-trioxotetrahydro-1,2,5-thiadiazol-2-yl,4,5-di(methoxycarbonyl)-1,2,3-triazin-1-yl,5-phenylsulfonyl-1,2,3-triazol-1-yl,4-trimethylsilyl-5-phenylsulfonyl-1,2,3-triazol-1-yl,4-methoxycarbonyl-1,2,3-triazol-1-yl,5-methoxycarbonyl-1,2,3-triazol-1-yl,4-ethoxycarbonyl-5-phenyl-1,2,3-triazol-1-yl,4-phenyl-5-ethoxycarbonyl-1,2,3-triazol-1-yl,4-carboxy-1,2,3-triazol-1-yl,4-phenyl-5-(4-methylphenylsulfonyl)-1,2,3-triazol-1-yl,4-(4-methylphenylsulfonyl)-5-phenyl-1,2,3-triazol-1-yl,4-phenylsulfonyl-1,2,3-triazin-1-yl,4-ethylsulfonyl-5-isopropyl-1,2,3-triazin-1-yl,4-isopropyl-5-ethylsulfonyl-1,2,3-triazin-1-yl,4,5-di(aminocarbonyl)-1,2,3-triazin-1-yl,4,5-dicarboxy-1,2,3-triazin-1-yl,4-trimethylsilyl-5-dimethylaminosulfonyl-1,2,3-triazol-1-yl,4-(1,1-dimethyl)ethyl-5-dimethylaminosulfonyl-1,2,3-triazol-1-yl,4-dimethylaminosulfonyl-5-(1,1-dimethyl)ethyl-1,2,3-triazol-1-yl,4-trimethylsilyl-1,2,3-triazol-1-yl,4-trimethylsilyl-5-methoxycarbonyl-1,2,3-triazol-1-yl,4-phenylsulfonyl-5-trimethylsilyl-1,2,3-triazol-1-yl,2-benzoyl-4,5-dibromoimidazol-1-yl,2-thioxo-2,3-dihydro-1,3,4-oxadiazol-3-yl,2-thioxo-2,3-dihydro-5-(2-pyridyl)-1,3,4-thiadiazol-3-yl,2,3-dihydro-2-oxo-5-phenyl-1,3,4-oxadiazol-3-yl,4,5-dicyano-1,2,3-triazol-1-yl,4,5-di(t-butylsulfonyl)-1,2,3-triazol-1-yl,4,5-di(1-piperidinylcarbonyl)-1,2,3-triazol-1-yl,4,5-di(trifluoromethyl)-1,2,3-triazol-1-yl,4,5-di(1-piperidinylcarbonyl)-1,2,3-triazol-2-yl,2-methylthio-5-methyl-6-oxo-1,2-dihydro-1,3,4-triazin-1-yl,3-benzyloxy-4,5-dihydro-5-oxo-1,2,4-oxadiazol-4-yl,1,2,5-thiadiazol-3-yl, 2-(4-methoxybenzoyl)indol-1-yl or2-methyl-3-(2,6-dichlorobenzoyl)indol-1-yl and R₃ is hydrogen or chloroand R₄ is hydrogen or 6-methoxy.
 5. A composition for the treatment ofdegenerative diseases selected from the group consisting of emphysema,rheumatoid arthritis and pancreatitis which comprises a pharmaceuticalcarrier and an effective proteolytic enzyme inhibiting amount of acompound having the formula ##STR6## wherein: R₁ is heterocyclylselected from 1H-(5-tetrazolyl), 5-oxo-1-tetrazolinyl,5-thioxo-1-tetrazolinyl when R₂ as defined hereinbelow is other thanphenylthio; pyimidinyl, 2-benzoxazolyl, 2-benzothiazolyl,2-phthalimidyl, 2-(1,3,4-thiadiazolyl), 5-(1,2,4-thiadiazolyl),5-thioxo-3-(1,2,4-thiadiazolinyl), 4-(5-oxo-1,3,4-thiadiazolinyl),4-(5-thioxo-1,3,4-thiadiazolinyl), 3-(1,2,4-triazolyl),4-(1,2,4-triazolyl), 1,2,3-triazol-1-yl, 2-imidazolyl,3-(1,2,4-triazolo[4,3-a]pyridinyl), pyridazin-3-yl, 4-pyron-3-yl,quinolin-8-yl, 1,3,4-oxadiazol-2-yl, coumarin-7-yl, saccharin-6-yl,imidazol-2-yl, 1,3,4-triazol-2-yl, thiazol-2-yl,2-thioxo-2,3-dihydro-1,3,4-oxadiazol-3-yl, 1,2,5-thiadiazol-3-yl,2-thioxo-2,3-dihydro-1,3,4-thiadiazol-3-yl,2-thioxo-2,3-dihydro-1,3,4-thiadiazol-5-yl, 1,2,3-triazol-2-yl,1,2,4-triazin-5-yl, 5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazin-3-yl,isoxazol-5-yl, isoxazol-3-yl, 5-oxo-1,2,4-oxadiazol-4-yl, pyridyl,1,1,3-trioxo-tetrahydro-1,2,5-thiadiazol-2-yl,6,7-dihydro-1H-1,2,4-triazolo[3,4-b][1,3]thiazin-3-yl,4,5-dihydro-5-oxo-1,2,4-oxadiazol-4-yl, 2,5-dioxopyrrolidin-1-yl,3-indolyl, oxazol-2-yl, thiazol-4-yl,2,3-dihydro-2-oxo-5-phenyl-1,3,4-thiadiazol-3-yl and2,3-dihydro-2-oxo-5-phenyl-1,3,4-oxadiazol-3-yl,or said heterocyclylsubstituted on any available nitrogen atom by lower-alkyl,hydroxy-lower-alkyl, cycloalkyl, 2-, 3- or 4-pyridinyl,carboxy-lower-alkyl, lower-alkoxycarbonyl-lower-alkyl,aminocarbonyl-lower-alkyl, lower-alkylaminocarbonyl-lower-alkyl,di-lower-alkylamino-carbonyl-lower-alkyl, amino-lower-alkyl,lower-alkylamino-lower-alkyl, di-lower-alkyl-amino-lower-alkyl,4-morpholinyl-lower-alkyl, 1-piperidinyl-lower-alkyl,1-pyrrolidinyl-lower-alkyl or phenyl or phenyl substituted by amino,lower-alkyl-amino, di-lower-alkylamino, lower-alkanamido,N-lower-alkyl-lower-alkanamido, carboxy-lower-alkanamido, carboxy,lower-alkoxycarbonyl, lower-alkoxy, halo or carboxy-lower-alkanoylamino,or said heterocyclyl substituted on any available carbon atom by nitro,lower-alkyl, amino, lower-alkylamino, di-lower-alkylamino,cycloalkylamino, mercapto, lower-alkylthio, amino-lower-alkylthio,lower-alkylamino-lower-alkylthio, di-lower-alkyl-amino-lower-alkylthio,4-morpholinyl-lower-alkylthio, 1-piperidinyl-lower-alkylthio,1-pyrrolidinyl-lower-alkylthio, lower-alkoxycarbonyl,di-lower-alkylamino-lower-alkyl, 4-morpholinyl-lower-alkylamino, cyano,1-piperidinyl-lower-alkyl, hydroxy-lower-alkyl, phenylsulfonyl,toluenesulfonyl, halo, tri-lower-alkylsilyl, carboxy or alkali metalsalt thereof, furyl, trifluoromethyl, 2-benzothiazolyl,lower-alkylsulfonyl, aminocarbonyl, benzyl, 4-morpholinyl, pyridinyl,lower-alkoxy, pyrazinyl, lower-alkoxycarbonyl-lower-alkyl,di-lower-alkylaminosulfonyl, 4-morpholinylcarbonyl, lower alkanoyl,benzyloxy, hydroxy, benzoyl or benzoyl substituted by lower-alkoxy orhalo, or phenyl or phenyl substituted by amino, lower-alkylamino,di-lower-alkylamino, lower-alkanamido, N-lower-alkyl-lower-alkanamido,lower-alkyl, lower-alkoxy, halo, trifluoromethyl,lower-alkoxy-poly-lower-alkoxy, methylenedioxy or lower alkoxycarbonyl;R₂ is hydrogen, lower-alkoxycarbonyl, phenyl or phenylthio; R₃ ishydrogen, halo, primary or secondary lower-alkyl, lower-alkoxy,lower-alkoxycarbonyl, phenyl, fluoro-lower-alkyl, lower-alkenyl, cyanoor di-lower-alkylamino; and R₄ is hydrogen or from one to threesubstituents selected from halo, cyano, nitro, amino, lower-alkanamido,phenyl-lower-alkanamido, diphenyl-lower-alkanamido,lower-alkylsulfonylamino, polyfluoro-lower-alkylsulfonylamino,aminosulfonyl, lower-alkyl, polyhalo-lower-alkyl, cycloalkyl,polyhalo-lower-alkoxy, hydroxy, lower-alkoxy, carboxy, hydroxymethyl,formyl, aminomethyl, lower-alkylsulfonyl, polyhalo-lower-alkylsulfonyl,lower-alkylsulfonyl-aminosulfonyl, lower-alkoxy-lower-alkoxy,lower-alkoxy-poly-lower-alkyleneoxy, carboxy-lower-alkoxy,lower-alkoxycarbonyl-lower-alkoxy or di-lower-alkylaminocarbonyloxy. 6.A composition according to claim 5 wherein:R₁ is2-methylthio-5-thioxo-1,3,4-thiadiazolin-4-yl, 2-phthalimidyl,5-[2-(1-piperidinyl)ethylthio]-2-thioxo-1,3,4-thiadiazolin-3-yl,4,5-dicyanoimidazol-1-yl, 1,1,3-trioxotetrahydro-1,2,5-thiadiazol-2-yl,4,5-di(methoxycarbonyl)-1,2,3-triazin-1-yl,5-phenylsulfonyl-1,2,3-triazol-1-yl,4-trimethylsilyl-5-phenylsulfonyl-1,2,3-triazol-1-yl,4-methoxycarbonyl-1,2,3-triazol-1-yl,5-methoxycarbonyl-1,2,3-triazol-1-yl,4-ethoxycarbonyl-5-phenyl-1,2,3-triazol-1-yl,4-phenyl-5-ethoxycarbonyl-1,2,3-triazol-1-yl,4-carboxy-1,2,3-triazol-1-yl,4-phenyl-5-(4-methylphenylsulfonyl)-1,2,3-triazol-1-yl,4-(4-methylphenylsulfonyl)-5-phenyl-1,2,3-triazol-1-yl,4-phenylsulfonyl-1,2,3-triazin-1-yl,4-ethylsulfonyl-5-isopropyl-1,2,3-triazin-1-yl,4-isopropyl-5-ethylsulfonyl-1,2,3-triazin-1-yl,4,5-di(aminocarbonyl)-1,2,3-triazin-1-yl,4,5-dicarboxy-1,2,3-triazin-1-yl,4-trimethylsilyl-5-dimethylaminosulfonyl-1,2,3-triazol-1-yl,4-(1,1-dimethyl)ethyl-5-dimethylaminosulfonyl-1,2,3-triazol-1-yl,4-dimethylaminosulfonyl-5-(1,1-dimethyl)ethyl-1,2,3-triazol-1-yl,4-trimethylsilyl-1,2,3-triazol-1-yl,4-trimethylsilyl-5-methoxycarbonyl-1,2,3-triazol-1-yl,4-phenylsulfonyl-5-trimethylsilyl-1,2,3-triazol-1-yl,2-benzoyl-4,5-dibromoimidazol-1-yl,2-thioxo-2,3-dihydro-1,3,4-oxadiazol-3-yl,2-thioxo-2,3-dihydro-5-(2-pyridyl)-1,3,4-thiadiazol-3-yl,2,3-dihydro-2-oxo-5-phenyl-1,3,4-thiadiazol-3-yl,2,3-dihydro-2-oxo-5-phenyl-1,3,4-oxadiazol-3-yl,4,5-dicyano-1,2,3-triazol-1-yl,4,5-di(t-butylsulfonyl)-1,2,3-triazol-1-yl,4,5-di(1-piperdinylcarbonyl)-1,2,3-triazol-1-yl,4,5-di(trifluoromethyl)-1,2,3-triazol-1-yl,4,5-di(1-pipeddinylcarbonyl)-1,2,3-triazol-2-yl,2-methylthio-5-methyl-6-oxo-1,2-dihydro-1,3,4-triazin-1-yl,3-benzyloxy-4,5-dihydro-5-oxo-1,2,4-oxadiazol-4-yl,1,2,5-thiadiazol-3-yl, 2-(4-methoxybenzoyl)indol-1-yl or2-methyl-3-(2,6-dichlorobenzoyl)indol-1-yl; R₂ is hydrogen; R₃ ishydrogen or chloro and R₄ is hydrogen or 6-methoxy.